MXPA04009689A - Benzamide derivatives useful as histone deacetylase inhibitors. - Google Patents

Benzamide derivatives useful as histone deacetylase inhibitors.

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Publication number
MXPA04009689A
MXPA04009689A MXPA04009689A MXPA04009689A MXPA04009689A MX PA04009689 A MXPA04009689 A MX PA04009689A MX PA04009689 A MXPA04009689 A MX PA04009689A MX PA04009689 A MXPA04009689 A MX PA04009689A MX PA04009689 A MXPA04009689 A MX PA04009689A
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Mexico
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carbon atoms
alkyl
group
carbon
amino
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MXPA04009689A
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Spanish (es)
Inventor
James Waring Michael
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Astrazeneca Ab
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Priority claimed from GB0207863A external-priority patent/GB0207863D0/en
Priority claimed from GB0229930A external-priority patent/GB0229930D0/en
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of MXPA04009689A publication Critical patent/MXPA04009689A/en

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Abstract

The invention concerns a compound of the formula (I) wherein Ring A is heterocyclyl; m is 0-4 and each R1 is a group such as hydroxy, halo, trifluoromethyl and cyano; R2 is halo and n is 0-2; and each R4 is a group such as hydroxy, halo, trifluoromethyl and cyano; p is 0-4; and R3 is amino or hydroxy; or pharmaceutically-acceptable salts or in-vivo-hydrolysable ester or amide thereof processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical condions mediated by histone deacetylase.

Description

- BENZAMIDE DERIVATIVES USEFUL AS HISTONE INHIBITORS _ DESACETILASE DESCRIPTION OF THE INVENTION This invention relates to benzamide derivatives, or pharmaceutically acceptable salts or in vivo hydrolysable esters or amides thereof. These benzamide derivatives possess histone deacetylase inhibitory activity (HDAC) and consequently have a value in the treatment of cancer-related disease state (Marks et al., Nature Reviews, 1, 194-202, (2001)), cystic fibrosis (Li, S. et al., J. Biol. Chem., 274, 7803-7815, (1999)), Huntingdons chorea (Steffan, JS et al., Nature, 413, 739-743, (2001)) and sickle cell anemia (Gabbianelli, M. et al., Blood, 95, 3555-3561, (2002)), and consequently are useful in methods of treating a homeothermic (warm-blooded) animal such as man. The invention also relates to processes for the manufacture of benzamide derivative, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for inhibiting HDAC in homeothermic animals, such as man. In the eukaryotic cell, the DNA is compacted to prevent the accessibility of the transcription factor. When the cell is activated, this compact DNA becomes available for the DNA-binding proteins, whereby the induction of gene transcription is allowed (Beato, MJ Med. Chem., 74, 711-724 (1996); Wolffe, AP, Nature, 387, 16-17 (1997)). Nuclear DNA is associated with histones to form a complex known as chromatin. The core histones, called H2A, H2B, H3 and H4 surrounded by 146 base pairs of DNA form the fundamental unit of chromatin, the nucleosome. The N-terminal tails of the core histones contain Usinas which are sites for posttranscriptional acetylation. Acetylation neutralizes the potential of the side chain to form a positive charge on the side chain of Usina and is considered to have an impact on the chromatin structure. Histone deacetylases (HDACs) are zinc-containing enzymes which catalyze the separation of acetyl groups from the e-amino end portions of lysine residues grouped near the amino terminal part of the nucleosomal histones. HDAC can be divided into two classes, the first (HDAC 1, 2, 3 and 8) represented by proteins similar to yeast Rpd3, and the second (HDAC 4, 5, 6, 7, 9 and 10) represented by proteins similar to yeast Hdal. The reversible procedure. for acetylation is important in the transcriptional regulation and progress of the cell cycle. HDAC dysregulation has been linked to several HDAC cancers and inhibitors, such as tricostina A (a natural product isolated from Streptomyces hygroscopicus), which has been shown to have significant antitumor effects and inhibition of cell growth (Meinke, PT, Current Medicinal Chemistry, 8, 211-235 (2001)). Yoshida et al., Exper. Cell Res., 177, 122-131 (1988) discloses that trichostatin A causes suppression of rat fibroblasts in the Gl and G2 phases of the cell cycle, by implicating HDAC in the regulation of the cell cycle. In addition, trichostatin A has been shown to induce terminal differentiation, inhibits cell growth and prevents the formation of tumors in mice (Finnin et al., Nature, 401, 188-193 (1999)). So far, few HDAC inhibitors are known in the art. Therefore, there is a need to identify additional HDAC inhibitors. Accordingly, the present invention provides a compound of the formula (I): (I) wherein: Ring A is a heterocyclyl, wherein if the heterocyclyl contains a -H- portion, this nitrogen may be optionally substituted by a group selected from K; R1 is a substituent on carbon and is selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2-amino, alkanoylamino of 1 to 6 carbon atoms, N-alkylcarbamoyl of 1 to 6 carbon atoms carbon, N, N- (alkyl of 1 to 6 carbon atoms) 2-carbamoyl, alkylS (0) a of 1 to 6 carbon atoms, wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms, N-Alkylsulfamoyl of 1 to 6 carbon atoms,?,? - (C 1 -C 6 alkyl) 2-sulfamoyl, aryl, aryloxy, arylalkyl of 1 to 6 carbon atoms, a heterocyclic group, (heterocyclic group) alkyl of 1 to 6 carbon atoms or a group (? -? - '), wherein R1 includes a group (BE-), which may be optionally substituted on the carbon by one or more of W; and wherein, if the heterocyclic group contains a -NH- portion, that nitrogen may optionally be substituted by JW is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2-amino, alkanoylamino of 1 to 6 carbon atoms, N-alkylcarbamoyl of 1 to 6 carbon atoms, N, N - (C 1-6 alkyl) 2-carbamoyl, alkyl S (0) a of 1 to 6 carbon atoms, wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms, N-alkylsulfamoyl of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2-sulfamoyl or a group (B'-E'-); wherein W which includes the group (B'-E1-), can optionally be substituted on the carbon by one more than Y; Y and Z are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, N, N- ( alkyl of 1 to 6 carbon atoms) 2-amino, alkanoylamino of 1 to 6 carbon atoms, N-alkylcarbamoyl of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2-carbamoyl, alkyl S (0) a of 1 to 6 carbon atoms, wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms, N-alkylsulfamoyl of 1 to 6 carbon atoms or N, N- (alkyl of 1 to 6) carbon atoms) 2-sulfamoyl; G, J and K are independently selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkanoyl of 1 to 8 carbon atoms, alkylsulfonyl of 1 to 8 carbon atoms, alkoxycarbonyl of 1 to 8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 1 to 8 carbon atoms, N, N-alkylcarbamoyl of 1 to 8 carbon atoms, benzyloxycarbonyl, benzoyl, phenylsulfonyl, aryl, arylalkyl of 1 to 6 carbon atoms or (heterocyclic group) ) alkyl of 1 to 6 carbon atoms; where G, J and K can be substituted - - optionally on the carbon by one or more of Q; and wherein if said heterocyclic group contains an -NH- moiety, the nitrogen may be optionally substituted by hydrogen or alkyl of 1 to 6 carbon atoms; Q is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms , alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to S carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 atoms carbon) 2-amino, alkanoylamino of 1 to 6 carbon atoms, N-alkylcarbamoyl of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2-carbamoyl, alkylS (0) of 1 to 6 carbon atoms, wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms, alkoxycarbonylamino of 1 to 6 carbon atoms, N-alkylsulfamoyl of 1 to 6 carbon atoms, N, N- (alkyl) 1 to 6 carbon atoms) 2-sulfamoyl, aryl, aryloxy, arylalkyl of 1 to 6 carbon atoms, arylalkoxy of 1 to 6 carbon atoms, a heterocyclic group, (heterocyclic group) -alkyl ilo of 1 to 6 carbon atoms, (heterocyclic group) alkoxy of 1 to 6 carbon atoms or a group (B → -E1 1-); wherein Q, which includes the group (? '' - E'1-) may optionally be substituted on the carbon by one - - or more of Z; B, B 'and B' 1 are independently selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl ( from 3 to 8 carbon atoms) -alkyl of 1 to 6 carbon atoms, aryl, arylalkyl of 1 to 6 carbon atoms, a heterocyclic group (heterocyclic group) -alkyl of 1 to 6 carbon atoms, phenyl or phenylalkyl 1 to 6 carbon atoms; wherein B, B 'and B1' may optionally be substituted on the carbon by one or more of D; and wherein if the heterocyclic group contains an -NH- moiety, that nitrogen may be optionally substituted by a group selected from G; E, E1 and E '1 are independently selected from -N (Ra) -, -O-, -C (0) 0-, -OC (O) -, -C (0) -, -N (Ra) C (0) -, -N (Ra) C (0) N (Rb) -, -N (Ra) C (0) 0-, -OC (0) N (Ra) -, -C (0) N (Ra) -, -S (0) r- , -S02N (Ra) -, -N (Ra) S02; wherein Ra and Rb are independently selected from hydrogen or alkyl of 1 to 6 carbon atoms, optionally substituted by one or more of F and r is 0-2; D and F are independently selected halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms carbon, alkanoyloxy of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2amino, alkanoylamino of 1 to 6 carbon atoms, N- alkylcarbamoyl of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2-carbamoyl, alkylS (0) to of 1 to 6 carbon atoms, where a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms, N-alkylsulfamoyl of 1 to 6 carbon atoms or N, N- (alkyl of 1 to 6 carbon atoms) 2-sulfamoyl; m is 0, 1, 2, 3 or 4; wherein the values of R1 may be the same or different; R2 is halo; n is 0, 1 or 2; wherein the values of R2 may be the same or different; R3 is amino or hydroxy; R4 is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms, alkynyl of 2 to 3 carbon atoms , alkoxy of 1 to 3 carbon atoms, alkanoyl of 1 to 3 carbon atoms, alkanoyloxy of 1 to 3 carbon atoms, N-alkylamino of 1 to 3 carbon atoms, N, N- (alkyl of 1 to 3 atoms) carbon) 2amino, - - alkanoylamino of 1 to 3 carbon atoms, N-alkylcarbamoyl of 1 to 3 carbon atoms, N, N- (alkyl of 1 to 3 carbon atoms) 2-carbamoyl, alkylS (0) of 1 to 3 carbon atoms , wherein a is 0 to 2, alkoxycarbonyl of 1 to 3 carbon atoms, N- (alkyl of 1 to 3 carbon atoms) sulfamoyl, N, N- (alkyl of 1 to 3 carbon atoms) 2-sulfamoyl; p is 0, 1 or 2; wherein the values of R4 may be the same or different, - or a pharmaceutically acceptable salt or an ester or amide hydrolysable in vivo thereof; with the proviso that the compound is not N- (2-amino-6-hydroxyphenyl) -4- (1-methylhomopiperazin-4-yl) benzamide; N- (2-amino-6-methylphenyl) -4- (1-methylhomopiperazin-4-yl) benzamide; N- (2-aminophenyl) -4- (1-terbutoxycarbonylhomopiperazin-4-yl) benzamide; or N- (2-aminophenyl) -4- (1-methylhomopiperazin-4-yl) benzamide; According to a further aspect of the present invention, there is provided a compound of formula (I), wherein: ring A is a heterocyclyl; R1 is halo, nitro, cyano, hydroxy, - - trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2amino, alkanoylamino of 1 to 6 carbon atoms, N-alkylcarbamoyl of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2carbamoyl, alkyls (0) to of 1 to 6 carbon atoms, where a is 0 or 2, alkoxycarbonyl 1 to 6 carbon atoms, N- (alkylsulfamoyl of 1 to 6 carbon atoms), N, N- (alkyl of 1 to 6 carbon atoms) 2-sulfamoyl or a group (B-E-); wherein, B is selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl (of 3 to 8 carbon atoms) alkyl of 1 to 6 carbon atoms, phenyl, heterocyclyl, phenylalkyl of 1 to 6 carbon atoms or heterocyclylalkyl of 1 to 6 carbon atoms; wherein B may optionally be substituted on the carbon by one or more of D; and wherein, if the heterocyclic contains a -NH- portion, this nitrogen may be optionally substituted by a group selected from G; E is -N (Ra) -, -O-, -C (0) 0-, -OC (O) -, -C (O) -, -N (Ra) C (0) -, C (0) N (Ra) -, -S (0) r-, -S02N '(Ra) -, -N (Ra) S02; wherein Ra is hydrogen or alkyl of 1 to 6 carbon atoms, optionally substituted by one or more of D and r is 0-2; D is independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2-amino, alkanoylamino of 1 to 6 carbon atoms, N-alkylcarbamoyl of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2carbamoyl alkylS (0) to 1 to 6 carbon atoms, wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms, N-alkylsulfamoyl of 1 to 6 carbon atoms and N, N- (alkyl of 1 to 6 carbon atoms) 2- sulfamoyl; G is selected from alkyl of 1 to 4 carbon atoms, alkanoyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, carbamoyl, N-alkylcarbamoyl of 1 to 4 atoms carbon, N, N (C 1 -C 4 alkyl) 2-carbamoyl, benzyl, benzyloxycarbonyl, benzoyl - - or phenylsulfonyl; m is 0, 1, 2, 3 or 4; wherein the values of R1 may be the same or different; R2 is halo; n is 0, 1 or 2; where the values of R2 can be the same or different; R3 is amino or hydroxy; R4 is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms, alkynyl of 2 to 3 carbon atoms , alkoxy of 1 to 3 carbon atoms, alkanoyl of 1 to 3 carbon atoms, alkanoyloxy of 1 to 3 carbon atoms, N-alkylamino of 1 to 3 carbon atoms, N, N- (alkyl of 1 to 3 atoms) carbon) 2-amino, alkanoylamino of 1 to 3 carbon atoms, N-alkylcarbamoyl of 1 to 3 carbon atoms, N, N- (alkyl of 1 to 3 carbon atoms) 2-carbamoyl, alkylS (0) of 1 to 3 carbon atoms, wherein a is 0 to 2, alkoxycarbonyl of 1 to 3 carbon atoms, N-alkylsulfamoyl of 1 to 3 carbon atoms), N, N- (alkyl of 1 to 3 carbon atoms) 2 sulphamoyl, p is 0, 1 or 2; wherein the values of R4 may be the same or different; or a pharmaceutically acceptable salt or an ester - or hydrolysable amide in vivo thereof; with the proviso that the compound is not N- (2-amino-6-hydroxyphenyl) -4- (1-methylhomopiperazin-4-yl) benzamide; N- (2-amino-6-methylphenyl) -4- (l-methylhomopiperazin-4-yl) benzamide; N- (2-Aminophenyl) -4- (1-tert.butoxycarbonylhomopiperazin-4-yl) benzamide; or N- (2-aminophenyl) -4- (l-methylhomopiperazin-4-yl) benzamide; In this specification, the term "alkyl" includes both straight and branched chain alkyl groups. For example, "alkyl of 1 to 8 carbon atoms" and "alkyl of 1 to 6 carbon atoms" include methyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl and tertbutyl. However, references to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched chain alkyl groups such as "isopropyl" are specific for the branched chain version only. The term "halo" refers to fluorine, chlorine, bromine and iodine. When selecting optional substituents from "one or more" groups, it is to be understood that this definition includes all substituents that are selected from one of the specified groups or substituents that are selected from two or more of the specified groups. A "heterocyclyl" is a monocyclic or saturated bicyclic, partially saturated or unsaturated ring containing 3 to 12 atoms of which at least one atom is selected from nitrogen, sulfur or oxygen, which, unless otherwise specified, it may be attached to carbon or nitrogen, wherein a sulfur atom in the ring may be optionally oxidized to form the S-oxide. Preferably, a "heterocyclyl" is a partially saturated or unsaturated saturated monocyclic ring containing 5 or 6 atoms of which at least one atom is selected from nitrogen, sulfur or oxygen or an 8 to 10 membered bicyclic ring, which, unless otherwise specified, it may be attached to carbon or nitrogen, wherein the sulfur atom in the ring may be optionally oxidized to form the S-oxide. Examples and suitable values of the term "heterocyclic" are thiazolidinyl, pyrrolidinyl, 1,3-benzodioxolyl, 1, 2, 4-oxadiazolyl, 2-azabicyclo [2.2.1] heptyl, morpholinyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, piperidinyl, piperazinyl , thiomorpholinyl, 1,3-dioxolanyl, homopiperazinyl, thienyl, pyrrolyl, pyrazolyl, oxadiazolyl, tetrazolyl, oxazolyl, thienopyridiminyl, thienopyridinyl, - thieno [3, 2d] pyrimidinyl, 1,3,5-triazinyl, purinyl, 1,2,3, 4 -tetrahidroquinolinilo, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzothienyl, benzofuranyl, indazolyl, quinazoliniloi cinnolinyl, phthalazinyl, quinoxalinyl, iridinilo naf, benzotriazolyl, pirrolotienilo, imidazotienilo, isoxazolyl, imidazolyl, thiadiazolyl, isothiazolyl, 1, 3, 3-triazolyl, 1,2,4-triazolyl, pyranyl, indolyl, pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl, quinolyl, quinazole nyl and 1- isoquinolinyl. A "heterocyclic group" is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring containing 3 to 12 atoms of which at least one atom is selected from nitrogen, sulfur or oxygen, which, unless otherwise specified Thus, it may be attached to the carbon or nitrogen, wherein a CH2 group may be optionally substituted by a C (O), and wherein a sulfur atom in the ring may optionally be oxidized to form the S-oxide. Preferably, "a heterocyclic group" is a saturated, partially saturated or unsaturated monocyclic ring containing 5 or 6 atoms of which at least one atom is selected from nitrogen, sulfur or oxygen or a 9 or 10 membered bicyclic ring which , unless otherwise specified, can be carbon or attached nitrogen, wherein a - CH2 group can optionally be substituted by a C (0), and wherein a sulfur atom in the ring can be optionally oxidized to form the S-oxide. Examples and suitable values of the term "heterocyclic group" are pyrrolidinyl, 2-pyrrolidonyl 2, 5-dioxopyrrolidinyl, 2,4-dioxoimidazolidinyl, 2 -oxo-1,3,4-riazolinyl, oxazolidinyl, 2-oxazolidonyl, 5,6-dihydrouracil, 1,3-benzodioxolyl, 1, 2, 4-Oxadiazolyl, 2-azabicyclo [2.2.1] heptyl, morpholinyl, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, piperidinyl, piperazinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, 1,3-dioxolanyl, homopiperazinyl, thiophenyl, thienopyridinyl, thienopyrimidinyl, thieno [3, 2d] pyrimidinyl, 1,3,5-triazinyl, purinyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, tetrahydroisoquinolinyl, imidazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl, indazolyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, naphthyridinyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, isothiazolyl, 1, 2, 3-triazolyl, 1, 2,4-triazolyl, pyranyl, indolyl, isoindolyl, pyrimidinyl, thiazolyl, pyrazolyl, 3-pyrrolinyl, pir azinyl, pyridazinyl, pyridinyl, pyridonyl, pyrimidonyl and 1-isoquinolinyl.
- An "aryl" group is, for example, phenyl, indenyl, indanyl, naphthyl, tetrahydronaphthyl or fluorenyl, preferably phenyl. An example of "C 1 -C 6 alkanoyloxy" is acetoxy. Examples of "aycarbonyl of 1 to 8 carbon atoms", "aycarbonyl of 1 to 6 carbon atoms" and "aycarbonyl of 1 to 4 carbon atoms" include methoxycarbonyl, ethoxycarbonyl and n- and t-butoxycarbonyl. Examples of alkynyl of 2 to 6 carbon atoms are ethynyl and 2-propynyl. Examples of "C 1 -C 6 ay" include methoxy, ethoxy and propoxy. Examples of "C 1 -C 6 -alkanoylamino" and "C 1 -C 3 -alkanoylamino" include formamido, acetamido and propionylamino Examples of "alkyl (0) a of 1 to 6 carbon atoms, wherein is 0 to 2"include alkylsulfonyl of 1 to 4 carbon atoms, alkylS (0) to 1 to 3 carbon atoms, methylthio, ethylthio, metisulfinyl, ethylsulfinyl, mesyl and ethylsulphonyl Examples of" alkanoyl of 1 to 8 atoms carbon "," C 1 -C 6 -alkanoyl "and" C 1 -C 4 -alkanoyl "include alkanoyl of 1 to 3 carbon atoms, propionyl and acetyl, examples of N-alkylamino of 1 to 6 atoms carbon "and" N-alkylamino of 1 to 3 carbon atoms "include methylamino and ethylamino. Examples of "N, N- (1 to 6 carbon atoms) 2-amino" and "N, N- (1 to 2 carbon atoms) 2-amino" include di-IV-methylamino , di- (N-etiDamino, di- (N-butyl) amino and .W-ethyl-IV-methylamino The examples of "alkenyl of '2 to 8 carbon atoms" are alkenyl of 2 to 6 carbon atoms and alkenyl of 2 to 3 carbon atoms, and include vinyl, allyl and 1-propenyl The examples of "iV-alkylsulfamoyl of 1 to 8 carbon atoms" and "iV-alkylsulfamoyl of 1 to 6 carbon atoms" are IV- alkylsulfamoyl of 1 to 3 carbon atoms, N-methylsulfamoyl and N-ethylsulphamoyl Examples of "N- (C 1-6 alkyl) 2-sulfamoyl" are N, N- (alkyl of 1 to 3 carbon atoms) carbon) 2-sulfamoyl, N, N-dimethylsulphamoyl and W-methyl-N-ethylsulphamoyl Examples of "N-alkylcarbamoyl of 1 to 8 carbon atoms" and "N-alkylcarbamoyl of 1 to 6 carbon atoms" are N -alkylcarbamoyl of 1 to 4 carbon atoms, iV-alkylcarbamoyl of 1 to 3 carbon atoms carbon, methylaminocarbonyl and ethylaminocarbonyl. Examples of "N, N- (alkyl of 1 to 8 carbon atoms) 2-carbamoyl" and "N, N- (alkyl of 1 to 6 carbon atoms) 2-carbamoyl" are N, N- (alkyl of 1 to 4 carbon atoms) -carbamoyl, N, N- (alkyl of 1 to 2 carbon atoms) 2-carbamoyl, dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of 11 (heterocyclic group) alkyl of 1 to 6 carbon atoms "include piperidin-1-ylmethyl, piperidin-1 - iletyl, piperidin-1-ylpropyl, pyridylmethyl, 3-morpholinopropyl, 2-morpholinoethyl and 2-pyrimid-2-ylethyl. Examples of "(heterocyclic group) ay of 1 to 6 carbon atoms" include (heterocyclic group) methoxy, (heterocyclic group) ethoxy and (heterocyclic group) propoxy. Examples of "arylalkyl of 1 to 6 carbon atoms" include benzyl, 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl. Examples of "aryloxy" include phenoxy and naphthyloxy. Examples of "3 to 8 carbon atoms" cycloalkyl include cyclopropyl and cyclohexyl. Examples of "cycloalkyl (3 to 8 carbon atoms) -alkyl of 1 to 6 carbon atoms" include cyclopropylmethyl and 2-cyclohexylpropyl. Examples of "aycarbonylamino of 1 to 6 carbon atoms" include methoxycarbonylamino and terbutoxycarbonylamino. Within this specification, the terms "compounds" are used to designate groups that comprise more than one functionality such as arylalkyl of 1 to 6 carbon atoms. Such terms must be interpreted and understood by those skilled in the art. For example arylalkyl of 1 to 6 carbon atoms comprises alkyl of 1 to 6 carbon atoms substituted by aryl and such group includes benzyl, 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl. A pharmaceutically suitable salt of a compound of the invention is, for example, an acid addition salt of a compound of the invention - which is sufficiently basic, for example, an acid addition salt with, for example , an inorganic or organic acid, for example acetic, hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, citric or maleic acid In addition, a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt , for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which provides a physiologically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine The compounds of formula (I) can be administered in the form of a hydrolyzate ester in vivo or an in vivo hydrolysable amide of a compound of the formula (I). An in vivo hydrolysable ester of a compound of the formula (I) which contains a carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the original acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include alkoxymethyl esters of 1 to 6 carbon atoms, for example methoxymethyl O, "esters of de-α-ketoyloxymethyl of 6 to 6 carbon atoms, for example pivaloyloxymethyl or phthalidyl esters, esters of cycloalkoxy (of 3 to 8 carbon atoms) carbonyloxyalkyl of 1 to 6 carbon atoms, for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-methylmethyl esters, for example 5-methyl-l, 3-dioxolen-2-onylmethyl; and alkoxycarbonyloxyethyl esters of 1 to 6 carbon atoms, for example 1-methoxycarbonyloxyethyl and can be formed in any carboxy group in the compounds of this invention. An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and -acryloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the decomposition of the ester they provide the original hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to provide alkyl carbonate esters), dialkylcarbamoyl and N- (N, W-dialkylaminoethyl) -N-alkylcarbamoyl (to provide carbamates), N, N- - - dialkylaminoacetyl and carbaxyacetyl. Examples of benzoyl substituents include morpholino and piperazino linked from a nitrogen atom in the ring by means of a methylene group to the 3 or 4 position of the benzoyl ring. A suitable value for an in vivo hydrolysable amide of a compound of the formula (I) containing a carboxy group is, for example, a V-alkyl of 1 to 6 carbon atoms, or N, N-di (alkyl) 1 to 6 carbon atoms) amide such as N-methylamide, N-ethylamide, N-propylamide, N, 2-V-dimethylamide, 2-V-ethyl-N-methyl amide or N, N-diethylamide. Some compounds of the formula (I) may have chiral centers and / or geometric isomeric centers (E and Z isomers), and it should be understood that the invention encompasses all such optical, diastereoisomeric and geometric isomers possessing HDAC inhibitory activity. The invention relates to any and all of the tautomeric forms of the compounds of the formula (I) which possess HDAC inhibitory activity. The additional values of the ring A, R1, R2, R3, R4, m, n and p are as follows. Such values may be used when appropriate with any of the definitions, claims or modalities defined in the foregoing or in the following.
Ring A is pyridyl, quinolyl, indolyl, pyrimidinyl, morpholinyl, piperidinyl, piperazinyl, pyrazinyl, pyrazinyl, thiazolyl, thienyl, thienopyrimidinyl, thienopyridinyl, purinyl, triazinyl, oxazolyl, pyrazolyl or furanyl; wherein, if ring A contains a portion -NH-, that nitrogen may be optionally substituted by a group selected from K. Ring A is pyridin-4-yl, pyridin-3-yl, pyridin-2-yl , quinolin-8-yl, pyridin-6-yl, pyrimidin-5-yl, pyrimidin-yl, morpholin-4-yl, piperidin-4-yl, piperidin-3-yl, piperidin-2-yl, piperazin- 4-yl, pyridazin-5-yl, pyrazin-6-yl, thiazol-2-yl, thien-2-yl, thieno [3, 2d] pyridinimethyl, thieno [3, 2b] pyrimidinyl, thieno [3, 2b] pyridinyl, purin-6-yl or triazin-6-yl; wherein if ring A contains a -NH- portion, that nitrogen may be optionally substituted by a group selected from K. Ring A is a pyridyl, quinolyl, pyrimidyl, morpholinyl, piperidinyl, piperazinyl, pyradiazinyl, pyrazinyl, thiazyl. or furanyl. Ring A is a pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, quinolin-8-yl, piradizin-2-yl, furan-3-yl, morpholinyl, thiazol-2-yl, pyrimidin -6-yl, piperidin-4-yl or piperazin-4-yl.
Ring A is pyridin-4-yl, pyridin-3-yl, quinolin-8-yl, piperidin-4-yl or piperazin-4-lc-R 1 is a substituent on carbon and is selected from halo, amino, 'alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, N-alkyl mino of 1 to 6 carbon atoms, aryl, aryloxy, arylalkyl of 1 to 6 carbon atoms, a heterocyclic group, (group heterocyclic) -alkyl of 1 to 6 carbon atoms, or a group (BE-); wherein R1, which includes the group (B-E-), may optionally be substituted on the carbon by one or more of; and wherein, if the heterocyclic group contains a -NH- portion, that nitrogen may be optionally substituted by J; W is hydroxy, mercapto, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2 amino or a group (B'-E'-) , - wherein W, which includes the group (B'-E'-) may optionally be substituted on the carbon by one or more of Y; Y and Z are independently selected from halo, nitro, cyano, hydroxy, alkoxy of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2-amino or alkanoylamino of 1 to 6 carbon atoms; G, J and K are independently selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkanoyl of 1 to 8 carbon atoms, - - aryl, arylalkyl of 1 to 6 carbon atoms or ( heterocyclic group) -alkyl of 1 to 6 carbon atoms; wherein "G, J and K may be optionally substituted on the carbon by one or more of Q, and wherein if the heterocyclic group contains a portion -NH-, that nitrogen may be optionally substituted by hydrogen or alkyl of 1 to 6 carbon atoms, Q is cyano, hydroxy, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkoxycarbonylamino of 1 to 6 carbon atoms, aryl, aryloxy or a group (? '' -? '' -) wherein Q, which includes the group (B ^ -E1 1-) may be optionally substituted on the carbon by one or more of Z; B, B 'and B " they are independently selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl (of 3 to 8 carbon atoms) -alkyl of 1 to 6 carbon atoms, aryl, arylalkyl of 1 to 6 carbon atoms, a heterocyclic group, (heterocyclic group) -al 1 to 6 carbon atoms, phenyl or phenylalkyl of 1 to 1 carbon atoms; wherein B, B1 and B "may optionally be substituted on the carbon by one or more of D; and wherein the heterocyclic group contains an -NH- moiety, that nitrogen may be optionally substituted by a group selected from G; - "| --|| - E, E 'and E' 1 are independently selected from -N (Ra) -, -O-, -C (0) 0-, -OC (0) -, -C (0 ) -, -N (Ra) C (0) -, -N (Ra) C (0) N (Rb) -, n- (Ra) C (0) 0-, -OC (O) N (Ra) -, -C (O) N (Ra) -, -S (0) r-, -S02N (Ra) -, -N (Ra) S02-; wherein Ra and Rb are independently selected from hydrogen or alkyl of 1 to 6 carbon atoms, optionally substituted by one or more of F and r is 0 to 2; D and F are independently selected from halo, alkoxy of 1 to 6 carbon atoms or N, N- (alkyl of 1 to 6 carbon atoms) 2-amino. R1 is a substituent on carbon and is selected from fluoro, chloro, amino, methyl, ethyl, propyl, methoxy, iV-methylamino, iV-ethylamino, W-propylamino, iV-butylamino, phenyl, naphthylethyl, piperazin-1-yl , piperidin-1-yl, piperidin-4-yl, 2- (thiomethyl) -pyrimidin-yl, tetrahydrofuran-2-ylmethyl, tetrahydropyran-2-ylmethyl, 1, 2, 5-thiadiazol-3-ylethyl, piperidin- 1-ylmethyl, pyridin-2-ylmethyl or a group (BE-); wherein R1, which includes the group (B-E-), may optionally be substituted on the carbon by one or more of W; and wherein, if the heterocyclic group contains a -NH- portion, that nitrogen may be optionally substituted by J; W is hydroxy, methyl, ethyl, ethoxy, N, N- (diethyl) amino, N, N- (dibutyl) araino or a group (B'-E1-); wherein W, which includes-the group (B '-E' - may be optionally substituted on the carbon by one or more of Y; Y and Z are independently selected from fluoro, chloro, bromo, nitro, cyanohydroxy, methoxy, N, N- (dimethyl) amino or methylcarbonylamino; G, J and K are independently selected from methyl, ethyl, propyl, pentyl, 2-methyl butyl, butyl, acetyl, benzyl, 3- (pyrrol-1-yl) propyl or pyrrolidin-2-one- (5S) -methyl, wherein G, J and K may be optionally substituted on the carbon by one or more of Q, and wherein if the heterocyclic group contains a -NH- portion, that nitrogen it may be optionally substituted by hydrogen or methyl, Q is cyano, hydroxy, methoxy, ethoxy, methylcarbonyloxy, methoxycarbonyl, tert-butoxycarbonylamino, phenyl or a group (α "- E1'-) wherein Q, which includes the group (B1 '- ? '' -) may optionally be substituted on the carbon by one or more of Z; B, B1 and B "are independently selected from methyl, ethyl, propyl, cyclohexyl, phenyl, benzyl, 1, 2, 3, 4-tetrahydroquinolinyl, 3-morpholinopropyl, 2-morpholinoethyl, 2-pyrrolidin-1-ylethyl, 3-morpholinopropyl, 3- (4-methylpiperazin-1-yl) propyl, -piperidin-1-ylethyl, 3-piperidin-1-ylpropyl, pyridin-3-ylmethyl or imidazol-1-ylpropyl; wherein B, B 'and B 1' can optionally be -substituted on the -carbon- by one or more of D; and wherein, if the heterocyclic group contains a -NH- moiety, that nitrogen may be optionally substituted by a group selected from G; E, E 'and E' 1 are independently selected from -N (Ra) -, -O-, -C (0) -, -NHC (O) -, -N (Ra) C (0) 0; wherein Ra is hydrogen or methyl optionally substituted by one or more of F; D and F are independently selected from fluoro, methoxy or ethoxy. R1 is a fluoro, chloro, amino, methyl, methoxy, 3-morpholin-4-ylpropylamino, (3-morpholin-4-yl) ethylamino, acetyl, benzyl, methoxycarbonylmethyl, 2-pyrrolidin-1-ylethoxy, 3-morpholinpropoxy, N- (2-fluorophenyl) propanamide, 4- (diethylamino) phenylcarbonylmethyl, 3- (4-methylpiperazin-1-yl) propylamino, 2-piperidin-1-ylethylamino, 2- [N, N- (diethyl) amino] ethylamino , pyridin-3-ylmethylarnino, 3-piperidin-1-ylpropylamino, imidazol-1-ylpropylamino, 3-methoxypropylamino, 3-morpholinpropylamino, piperazin-1-yl, N-ethylamino, 4-methylpiperazin-1-yl, 1- ( 3- phenoxy) ropyl, 1- (3-cyanophenyl) methyl, 1- (4-cyanophenyl) methyl, tetrahydrofuran-2-ylmethyl, 1- (3-benzyloxy) ropyl, 3-methoxybenzyl, 2,3-dihydroxypropyl, 2 - (methylcarbonyloxy) ethyl, 3- (pyrrol-1-yl) propyl, 1- [3- (2-methoxyethoxy)] propyl, 2- (4-acetamidophenoxy) ethyl, 2-. { t-butoxycarbonylamino) ethyl,. 2- (L-butoxycarbonylamino) ropyl, 2- [(2-methoxyphenyl) oxy] ethyl, (1,2,3,4-tetrahydroquinolin-1-yl) acetyl, 2 - [N- (2-fluoro-phenyl) -ylacetamide] ] ethyl, methoxycarbonylmethyl, 2- (ethoxy) ethyl, -methylpent -3-enyl, tetrahydropyran-2-methylmethyl, 1- (2S) -2-methylbutyl, 4- (benzyloxy) butyl, 2- [4- (nitro) phenoxy)] ethyl, 2 - [N, N- (dibutyl) amino] ethylamino, 3- [(iV-methyl-W-phenyl) amino] -propylamino,? G-3 - [2 - (dimethylamino) ethoxy] propylamino, 2- [4- (acetamido) phenoxy] ethyl, 2- [4- (hydroxyphenoxy)] ethyl, 1, 2, 5-thiadiazol-3-ethyl, piperidin-1-ylmethyl , 2- [4- (chloro) -phenoxy] ethyl, pyrrolidin-2-one- (5S) -methyl, phenylaminocarbonyloxymethyl, cyclohexylaminocarbonyloxymethyl, 2- (thiomethyl) -pyrimidin-4-yl or pyridin-2-ylmethyl. R1 is halo, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 1 to 3 carbon atoms, N-alkylamino of 1 to 3 carbon atoms, -V, N- ( alkyl of 1 to 3 carbon atoms) 2 amino, alkanoylamino of 1 to 3 carbon atoms, N-alkylcarbamoyl of 1 to 3 carbon atoms, N, N- (alkyl of 1 to 3 carbon atoms) 2carbamoyl. R1 is halo, amino, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms.
R1 is halo, amino, methyl or methoxy. The radical m is 0, 1, 2, 3, or 4; wherein the values of R1 may be the same or different. The radical m is 0 1 or 2; wherein the values of R1 may be the same or different. The radical m is o or 1. The radical m is 0. The radical m is 1. R2 is halo. R2 is fluoro or chloro. R2 is fluoro. The radical n is 0, 1 or 2, where the values of R2 can be the same or different. The radical n is 0 or 1. The radical n is 0. The radical n is 1. R3 is amino or hydroxy. R3 is amino. R3 is hydroxy. R 4 is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy or carbamoyl. R 4 is halo, cyano, trifluoromethyl or trifluoromethoxy. R4 is halo.
The radical p is 0, 1 or 2, wherein the values of R4 can be the same or different. The radical p is 0 or 1. The radical p is 0. ' The radical p is 1. Therefore, in a further aspect of the invention, there is provided a compound of formula (I) (as described above) wherein: Ring A is pyridyl, quinolyl, indolyl, pyrimidinyl, morpholinyl, piperidinyl, piperazinyl, pyrazinyl, pyrazinyl, thiazolyl, thienyl, thienopyrimidinyl, thienopyridinyl, purinyl, triazinyl, oxazolyl, pyrazolyl or furanyl; wherein, if ring A contains a -NH- portion, that nitrogen may be optionally substituted by a group selected from K. R1 is a substituent on carbon and is selected from halo, amino, alkyl of 1 to 6 atoms carbon, alkoxy of 1 to 6 carbon atoms, iV-alkylamino of 1 to 6 carbon atoms, aryl, aryloxy, arylalkyl of 1 to 6 carbon atoms, a heterocyclic group, (heterocyclic group) -alkyl of 1 to 6 carbon atoms, or a group (BE-) wherein R1, which includes the group (BE-), can optionally be substituted on the carbon by one or more of W; and wherein, if the heterocyclic group contains a -? - portion, that nitrogen may be optionally substituted by J; "- W is hydroxy, mercapto, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2aniino or a group (B'-E1- ), wherein W, which includes the group (B'-E'-) may be optionally substituted on the carbon by one or more of Y; Y and Z are independently selected from halo, nitro, cyano, hydroxy, alkoxy, to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2-amino or alkanoylamino of 1 to 6 carbon atoms; G, J and K are independently selected from alkyl of 1 to 8 carbon atoms , alkenyl of 2 to 8 carbon atoms, alkanoyl of 1 to 8 carbon atoms, aryl, arylalkyl of 1 to 6 carbon atoms or (heterocyclic group) -alkyl of 1 to 6 carbon atoms, wherein G, J and K may be optionally substituted on the carbon by one or more of Q, and wherein if the heterocyclic group contains an -NH- portion, that nitrogen may be optionally substituted by hydrogen or 1 to 6 carbon atoms; Q is cyano, hydroxy, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkoxycarbonylamino of 1 to 6 carbon atoms, aryl, aryloxy or a group (? '- -' '-) where Q, which includes the group (R 1 1 -R 1' -) can be - substituted - optionally on the carbon by one or more of Z; B, B 'and B "are independently selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl ( from 3 to 8 carbon atoms) -alkyl of 1 to 6 carbon atoms, aryl, arylalkyl of 1 to 6 carbon atoms, a heterocyclic group, (heterocyclic group) -alkyl of 1 to 6 carbon atoms, phenyl or phenylalkyl from 1 to 6 carbon atoms; wherein B, B 'and B' 1 may optionally be substituted on the carbon by one or more of D; and wherein if the heterocyclic group contains an -NH- portion, that nitrogen may be optionally substituted by a group selected from G; E, E1 and E1 'are independently selected from -N (Ra) - (-O-, -C (0) 0-, -0C (0) -, -C (0) -, -N (Ra) C ( 0) -, -N (Ra) C (0) N (Ra) N- (Ra) C (O) O-, -0C (O) N (Ra) -, -C (0) N (Ra) - , -S (0) r-, -S02N (Ra) -, -N (Ra) S02-; wherein R and Rb are independently selected from hydrogen or alkyl of 1 to 6 carbon atoms, optionally substituted by one or more of F and r is 0 to 2: D and F are independently selected from halo, C 1 -C 6 alkoxy or N, N- (alkyl from 1 to 6 - - carbon atoms) 2-amino; m is 0, 1, 2, 3 or 4; "where the values of R1 can be the same or different, R2 is fluoro or chlorine, n is 0, 1 or 2, where R2 values can be the same or different R3 is amino or hydroxy, R4 is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy or carbamoyl, p is 0, 1 or 2, wherein the values of R4 may be the same or different, or a salt pharmaceutically acceptable or an in vivo hydrolysable ester or amide thereof Thus, in a further aspect of the invention, there is provided a compound of formula (I) (as shown above) wherein: Ring A is pyridine -4-yl, pyridin-3-yl, pyridin-2-yl, quinolin-8-yl, pyrimidin-6-yl, pyrimidin-5-yl, pyrimidin-4-yl, morpholin-4-yl, piperidin-4 -yl, piperidin-3-yl, piperidin-2-yl, piperazin-4-yl, pyridazin-5-yl, pyrazin-6-yl, thiazol-2-yl, thieno-2-yl, thieno [3.2d] pyrimidinyl, thieno [3, 2b] pyrimidinyl, thieno [3, 2b] pyridinyl, purin-6-yl or triaz in-6-ilo; wherein if the ring A contains a portion -NH-, that-nitrogen may be optionally substituted by a group selected from ""; "R1 is a substituent on carbon and is selected from fluoro, chloro amino, methyl, ethyl, propyl, methoxy, N-methylamino, N-ethylamino, N-propylamino, N-butylamino, phenyl, naphthylethyl, piperazin-1-yl , piperidin-1-yl, piperidin-4-yl, 2- (thiomethyl) -pyrimidin-4-yl, tetrahydrofuran-2-ylmethyl, tetrahydropyran-2-ylmethyl, 1, 2, 5-thiadiazol-3-ylethyl, piperidin -l-ylmethyl, pyridin-2-ylmethyl or a group (BE-), wherein R1, which includes the group (BE-), may be optionally substituted on the carbon by one or more of W, and wherein, if the heterocyclic group contains a portion -NH-, that nitrogen may be optionally substituted by J, is hydroxy, methyl, ethyl, ethoxy, N, N- (diethyl) -amino, N, N- (dibutyl) amino or a group ( B'-E '-) (- where W, which includes the group (B'-E'-), can be optionally substituted on the carbon by one or more of Y; Y and Z are independently selected from fluoro, chloro , bromine, nitro, cyano, hydroxy, methoxy, N, N- (dimethyl) amino or methylcarbonylamino; G, J and K are independently selected from methyl, ethyl, propyl, pentyl, 2-methylbutyl, butyl, acetyl, benzyl, 3- (pyrrol-1-yl) -propyl or pyrrolidin-2-one- (5S) -methyl; wherein G, J and K may be optionally substituted thereon by one or more Q; and wherein if the heterocyclic group contains a -NH- portion, that nitrogen may be optionally substituted by hydrogen or methyl; Q is cyano, hydroxy, methoxy, ethoxy, methylcarbonyloxy, methylcarbonyl, terbutoxycarbonylamino, phenyl or a group (B "-E" -) wherein Q, which includes the group (B "-E" -), can be optionally substituted on the carbon by one or more of Z; B, B1 and B "are independently selected from methyl, ethyl, propyl, cyclohexyl, phenyl, benzyl, 1, 2, 3, 4-tetrahydroquinolinyl, 3-morpholinopropyl, 2-morpholinoethyl, 2-pyrrolidin-1-ylethyl, 3 - morpholinopropyl, 3- (4-methylpiperazin-1-yl) propyl, 2-piperidin-1-ylethyl, 3-piperidin-1-ylpropyl, pyridin-3-ylmethyl or imidazol-1-ylpropyl, wherein B, B 'and B "may optionally be substituted on the carbon by one or more of D; and wherein if the heterocyclic group contains an -NH- moiety, that nitrogen may be optionally substituted by a group selected from G; E, E 'and E "are independently selected from -N (Ra) -, -O-, -C (0) -, -NHC (O) -, -N (Ra) C (0) 0-; Ra is hydrogen or methyl optionally substituted by one or more of F; D and F are independently selected from fluoro, methoxy or etcxi; - - m is 0, 1 or 2; wherein the values of R1 may be the same or different; 2 is fluoro; n is 0 or 1; R3 is amino; R4 is halo; p is 0, 1 or 2, wherein the values of R4 may be the same or different; or a pharmaceutically acceptable salt or a hydrolysable ester in vivo or amide thereof. In another aspect of the invention, the preferred compounds of the invention are any of the examples, or a pharmaceutically acceptable salt or an ester or amide thereof hydrolysable in vivo. In another aspect of the invention, a compound of the formula (I) or a pharmaceutically acceptable salt thereof is provided. Another aspect of the present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, wherein (wherein the ring A, R1, R2, R3, R4, m, n and p are, unless otherwise specified, as defined in formula (I)) comprising: (a) The reaction of a compound of formula (II) (R2) n wherein X is a reactive group, with a compound of the formula (III) (R1), (III) wherein L1 and L2 are ligands; (b) The reaction of a compound of the formula (IV): R2) n wherein L1 and L2 are ligands, with a compound of the formula (V) - ÍR1), wherein X is a reactive group; or (c) The reaction in the presence of 4- (4,6-dimethoxy-1,3,5-triazinyl-2-yl) -4-methylmorpholinium chloride, of a compound of the formula (VI) with a compound of the formula (VII) and subsequently, if necessary: i) converting a compound of formula (I) to another compound of formula (I); and / or ii) removing any protecting group. A suitable base for processes (a), (b) or (c) is, for example, an organic amine base such as, "for example, pyridine, -2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo [5.. 0] undec-7-ene, or, for example, an alkali metal or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal hydride, for example sodium hydride or a metal alkoxide such as sodium ethoxide A suitable reactive group X is, for example, a halo, alkoxy group , aryloxy or sulfonyloxy, for example a chloro, bromo, methoxy, phenoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy or toluene-4-sulfonyloxy group The reactions are conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alkanol or ester such as methanol, ethanol, isopropanol or ethyl acetate it, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane, an aromatic solvent such as toluene or a dipolar aprotic solvent such as?, ? -dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2 -one or dimethyl sulfoxide. The reactions are conveniently carried out at a temperature in the range, for example, from 10 to 250 ° C, preferably in the range from 40 to 80 ° C. A suitable solvent for the ligands L1 and L2 which are present in the boron atom include, for example, a hydroxy ligand, alkoxy of 1 to 4 carbon atoms or alkyl of 1 to 6 carbon atoms, for example a hydroxy ligand , methoxy, ethoxy, propoxy, isopropoxy, butoxy, methyl, ethyl, propyl, isopropyl or butyl. Alternatively, the ligands L1 and L2 can be linked such that, together with the boron atom to which they are attached, they form a ring. For example, L1 and L2 together can define an oxy-alkylene-oxy group of 2 to 4 carbon atoms, for example an oxyethyleneoxy or oxytrimethyleneoxy group such that, together with the boron atom to which they are attached, they form a group of cyclic boronic acid ester. A catalyst suitable for process (a) or (b) includes, for example, a metal catalyst such as palladium (O), palladium (II), nickel (0) or nickel (II) catalyst, for example tetrakis (triphenylphosphine) ) aladium (0), palladium (II) chloride, palladium (II) bromide, bis (triphenylphosphine) palladium (II) chloride, tetrakis (triphenylphosphine) -nickel (0), nickel (II) chloride, bromide nickel (II) or bis (triphenylphosphine) nickel (II) chloride. In addition, an initiator can be conveniently added by free radicals, for example an azo compound such as azo (bisisobutyronitrile). It will be appreciated that some of the various ring substituents in the compounds of the present invention can be introduced by standard aromatic substitution reactions or can be generated by conventional modifications of functional groups either before or immediately after the aforementioned process, and as such they are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction., reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and the reaction conditions for such processes are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and a Lewis acid (such as aluminum trichloride) under Friedel-Crafts; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminum trichloride) under Friedel-Crafts conditions; and the introduction of a halo group. Particular examples of modifications include the reduction of a nitro group to an amino group, for example, by catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid, with heating; oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl. It will also be appreciated that some of the reactions mentioned herein may be necessary / desirable to protect any sensitive group in the compounds. Cases where protection is necessary or desirable and methods suitable for protection are known to those skilled in the art. Conventional protecting groups can be used in accordance with standard practice (for illustration see T. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Therefore, if the reagents include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein. A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl group, ethoxycarbonyl or terbutoxycarbonyl, an arylmethoxycarbonyl group, for example benzyloxycarbonyl an aroyl group, for example benzoyl. The deprotection conditions for the protective-anterior groups necessarily vary with the choice of the protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group can be separated, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. . Alternatively, an acyl group such as a tert-butoxycarbonyl group can be separated, for example, by treatment with a suitable acid such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group, for example, can be removed. by hydrogenation on a catalyst such as palladium on carbon or, by treatment with a Lewis acid, for example boron tris (trifluoroacetate). An alternative protecting group suitable for a primary amino group is, for example, a phthaloyl group which can be separated by treatment with an alkylamine, for example dimethylaminopropylamine or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as an acetyl or aroyl group, for example benzoyl or an arylmethyl group, for example benzyl. The deprotection conditions of the above protecting groups will necessarily vary with the selection of the protecting group. In this way, for example, an acyl group such as alkanoyl or an aroyl group can be separated, for example by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an arylmethyl group such as a benzyl group can be separated, for example by hydrogenation over a catalyst such as palladium on carbon. A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or ethyl group which can be separated, for example, by hydrolysis with a base such as sodium hydroxide or for example a tert.butyl group which can be separated, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid or, for example, a benzyl group which can be separated, for example, by hydrogenation on a catalyst such as palladium on carbon . The protecting groups can be separated at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
Biological Assays The following assays can be used to measure the effects of the compounds of the present invention as HDAC inhibitors, as accumulative histone deacetylase inhibitors - ± n vitro for nuclear extracts prepared from the human cervical cancer cell line HeLa , as in vitro inhibitors of recombinant human HDAC1 produced in Hi5 insect cells and in vitro inducers of histone H3 acetylation in whole cells. (a) In vitro enzyme assay of accumulated histone deacetylases HDAC inhibitors are screened against histone deacetylases accumulated from nuclear extracts of the HeLa human cervical cancer line. The deacetylase assays are carried out in 40 μ? of reaction. 2.5 μ? of nuclear extract diluted in 15 μ? of reaction buffer (25 mM Tris HCl (pH 8), 137 mM NaCl, 2.7 mM KC1, and 1 mM MgCl2) is mixed with either 5 μm of shock absorber alone or with 5 μ? of buffer containing compound, for 30 minutes, at room temperature. Then 25 μ? Is added to the reaction. of substrate fluor-de-lys (Biomol) diluted in 20 μ? of buffer and incubated for one hour at room temperature. The reaction is stopped by the addition of an equal volume (40 μ?) Of the fluor-de-lys (Biomol) developer containing trichostatin A at 2 μ. The reaction is allowed to proceed for 30 minutes at room temperature and then the fluorescence is measured in an excitation wavelength determination equipment of 360 nm and an emission wavelength of 465 nm. The IC50 values for the HDAC enzyme inhibitors were determined by performing dose versus response curves with individual compounds and by determining the inhibitor concentration that produces a 50 percent decrease in the maximum signal (without inhibitor control). (b) In Vitro Enzyme Assay of Recombinant HDAC1 The HDAC inhibitors were screened against human recombinant HDAC1 produced in Hi5 insect cells. The enzyme is cloned with a FLAG tag in the C-terminal part of the gene and purified by affinity using agarose against FLAG M2 from SIGMA (A2220). The deacetylase assays are carried out in 50 μ? of reaction. 75 ng of enzyme diluted in 15 μ? Reaction buffer (25 nM Tris HCl (pH 8), 137 mM NaCl, 2.7 mM KC1, and 1 mM MgCl2) either with 5 μ? shock absorber alone or with 101 buffer containing compound, for 30 minutes, at room temperature. Then 50 μ? Are added to the reaction. of fluoro-de-lys substrate (Biomol) diluted in 25 μ? of shock absorber and se - -. incubated for one hour at room temperature. "The reaction is stopped by adding an equal volume (50 μm) of the fluor-de-lys developer (Biomol) containing trichostatin A 5 to 2 μm. develop for 30 minutes at room temperature and then measure the fluorescence at an excitation wavelength of 360 nm and an emission wavelength of 465 nm.The IC50 values for the HDAC enzyme or inhibitors were determined by making curves of dose versus response with individual compounds and when determining the concentration of inhibitor that produces a 50 percent decrease in the maximum signal (without inhibitory control). 15 (c) In Vitro Enzyme Assay of Histone Deacetylase Activity in Whole Cells The histone H3 acetylation activity in whole cells was determined using immunohistochemistry and analysis using the 20 arrangements (arrayscan) Cellomics. A549 cells were seeded in 96-well plates at a concentration of 1 x 10 4 cells / well and allowed to adhere overnight. Then treated with inhibitors for 24 hours and then fixed in formaldehyde 1.8% in solution 25 saline buffered with Tris (TBS) for one hour. The cells were permeabilized with ice-cooled methanol for 5 minutes, rinsed with TBS and then blocked in TBS with 3% low fat dry milk., for 90 minutes. Subsequently the cells are incubated with polyclonal antibodies specific for acetylated histone H3 (Upstate # 06-599) diluted 1 in 500 in TBS with 3% milk for one hour. The cells are rinsed three times in TBS and then incubated with fluorescein-conjugated secondary antibodies (Molecular Probes # A11008) and Hoechst 333542 (1 g / ml) (Molecular Probes # H3570) in TBS 1% bovine serum albumin (Sigma # B6917 ) for an hour. The unbound antibody is separated by three rinses with TBS and then the final 100 μl rinse is added. of TBS to the cells and the plates are sealed and analyzed using the Cellomics array scan. The IC50 values for HDAC inhibitors were determined by performing the dose versus response curves with individual compounds and then determining the concentration of inhibitor that produces 50 percent of the maximum signal (control reference compound trichostatin A (Sigma)). Although the pharmacological properties of the compounds of the formula (I) vary with the structural change as expected, in general the activity possessed by the compounds of the formula I can be demonstrated at the following concentrations or doses in one or more of the tests previous (a) and (b): * Test (a): IC50 in the interval, for example from <; 50.0 μ; Test (b): CIS0 in the interval, for example from < 2.5 μ ?; Test (c): IC50 in the range, for example from < 9.0 μ ?; According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt or an ester or amide hydrolysable in vivo thereof, as defined above, in association with a pharmaceutically acceptable diluent or carrier. The composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion administration) as a sterile form of a solution, suspension or emulsion , for topical administration or as an ointment or cream or for rectal administration as a suppository. In general, the above compositions can be prepared in a conventional manner using conventional excipients. The compound of formula (I) will normally be administered to a horneothermic animal at a unit dose within the range of 5-5000 mg per square meter of animal body area, i.e. about 0.1-100 mg / kg, and this usually provides a therapeutically effective dose. A unit dose from such, such as a tablet or capsule, will usually contain, for example, 1-250 mg of active ingredient. Preferably a daily dose in the range of 1-50 mg / kg is used. However, the daily dose will necessarily vary depending on the host treated, the particular route of administration and the severity of the disease being treated. Consequently, the optimal dosage can be determined by the practicing physician who treats any particular patient. We have found that the compounds defined in the present invention, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester or amide thereof, are effective inhibitors of the cell cycle (agents against cell proliferation), property which is considered to arise from their HDAC inhibitory properties. We also believe that the compounds of the present invention can be involved in the inhibition of angiogenesis, activation of apoptosis and differentiation. Accordingly, the compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions mediated alone or in part by HDAC enzymes, that is, the compounds can be used to produce an inhibitory effect. of HDAC in a homeothermic animal in need of such treatment. In this manner, the compounds of the present invention provide a method for treating the proliferation of malignant (cancer) cells, characterized by inhibition of HDAC enzymes, ie, the compounds can be used to produce a mediated antiproliferative effect alone or in part by inhibition of HDAC. In accordance with one aspect of the present invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or an ester or amide thereof hydrolysable in vivo, as defined above, for use in a method of treatment of the human or animal body by therapy. Thus, according to a further aspect of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt or ester or amide thereof hydrolysable in vivo, as defined above, for use as a medicament. . According to one aspect of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt or an ester or amide of the - in vivo hydrolysable, as defined above, in the manufacture of a medicament for use in the production of an HDAC inhibitory effect in a homeothermic animal such as man. According to a further feature of this aspect of the invention, there is provided a method for producing an HDAC inhibitory effect in a homeothermic animal, such as man, in need of such treatment, which comprises administering to the animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an ester or amide thereof hydrolysable in vivo, as defined above. According to one aspect of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt or an ester or amide thereof in vivo hydrolysable, as defined above, in the preparation of a medicament for use in the production of a cell cycle inhibitory effect (against cell proliferation) in a homeothermic animal, such as man. According to a further feature of this aspect of the invention, a method is provided for producing a cell cycle inhibitory effect (against the Cell proliferation) in a homeothermic animal, such as man, in need of such treatment, which comprises administering to the animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an ester or amide of the same hydrolysable in vivo, as defined in the above. According to a further feature of this aspect of the invention, a method is provided for treating cancer in a homeothermic animal, such as man, in need of such treatment, which comprises administering to the animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an ester or amide thereof hydrolysable in vivo, as defined above. According to a further feature of the invention, there is a compound 74a of the formula (I) or an acceptable salt or an ester or amide thereof hydrolysable in vivo, as defined above, in the manufacture of a medicament for use in the treatment of cancer. According to a further feature of this aspect of the invention, there is provided a compound of the formula (I) or a pharmaceutically acceptable salt or an ester or amide thereof in vivo hydrolysable, as defined above, for use in the cancer treatment. In a further aspect of the present invention, there is provided the use of a compound of formula (I) or a pharmaceutically-acceptable salt or a hydrolyzable ester in vivo or an amide thereof, as defined above, in the preparation of a drug for use in lung cancer, colorectal cancer, breast cancer, prostate cancer, lymphoma and leukemia. In a further aspect of the present invention, there is provided a method for treating lung cancer, colorectal cancer, breast cancer, prostate cancer, lymphoma or leukemia in a homeothermic animal, such as man, in need of such treatment, characterized because it comprises administering to the animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a hydrolysable ester in vivo or an amide thereof, as defined above. Cancers that are amenable to treatment with the present invention include esophageal cancer, myeloma, hepatocellular, pancreatic and cervical cancer, Ewings tumor, neuroblastoma, kaposis sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, cancer. bladder, melanoma, lung cancer [including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)], gastric cancer, head and neck cancer, brain cancer, kidney cancer, lymphoma and leukemia .
A compound of the formula (I) or a pharmaceutically-acceptable salt or an ester or amide hydrolysable in vivo thereof is further provided., as defined in the foregoing, for use in a method for treating inflammatory diseases, autoimmune diseases and allergic-atopic diseases. In particular, there is provided a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester or amide thereof, as defined above, for use in a method of treating joint inflammation (especially arthritis). rheumatoid, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), inflammation of the skin (especially psoriasis, eczema and dermatitis), multiple sclerosis, atherosclerosis, spondyloarthropathies (ankylosing spondylites, psoriatic arthritis, arthritis related to ulcerative colitis), neuropathies related to AIDS, systemic lupus erythematosus, asthma, chronic obstructive pulmonary diseases, bronchitis, pleuritis, adult respiratory distress syndrome, septicemia and acute and chronic hepatitis (viral, bacterial or toxic). There is further provided a compound of the formula (I) or a pharmaceutically acceptable salt or an ester or amide hydrolysable in vivo thereof, as defined above, - for use as-a-medicament 'and -the treatment of inflammatory diseases, autoimmune diseases and allergic / atopic diseases in a homeothermic animal such as man. In particular, there is provided a compound of the formula (I) or a pharmaceutically acceptable salt or an ester or amide hydrolysable in vivo thereof, as defined above, for use as a medicament in the treatment of inflammation of the joints ( especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially bowel disease, ulcerative colitis and gastritis), inflammation of the skin (especially psoriasis, eczema and dermatitis), multiple sclerosis, atherosclerosis, spondyloarthropathies (ankylosing spondylitis, psoriatic arthritis, arthritis related to ulcerative colitis), neuropathies related to AIDS, systemic lupus erythematosus, asthma, chronic obstructive pulmonary diseases, bronchitis, pleuritis, adult respiratory distress syndrome, septicemia and acute and chronic hepatitis (viral, bacterial or toxic). There is further provided the use of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester or amide thereof, as defined above, in the manufacture of a medicament for the treatment of inflammatory diseases, autoimmune diseases and allergic / atopic diseases in a homeothermic animal such as man. As stated in the foregoing, the size of the dose required for the therapeutic or prophylactic treatment of a particular cell proliferation disease will necessarily vary based on the treated host, the route of administration and the severity of the disease being treated. A unit dose in the range is considered, for example, from 1 to 100 mg / kg, preferably from 1 to 50 mg / kg. The HDAC inhibitory activity defined as in the above, can be applied as a single treatment or can involve, in addition to a compound of the invention, one or more substances or treatments. Such joint treatment can be obtained by means of simultaneous, sequential or separate administration of the individual components of the treatment. In the field of medical oncology, it is normal practice to use a combination of different forms of treatment to treat each patient with cancer. In medical oncology, one or more of the other components of such joint treatment in addition to the cell cycle inhibitor treatment defined in the above may be: surgery, radiotherapy or chemotherapy.
Chemotherapy may include one or more of the following categories of antitumor agents: (i) other cell cycle inhibiting agents that work by mechanisms the same or different from those defined above, for example cyclin-dependent kinase (CDK) inhibitors in in particular CDK2 inhibitors: (ii) cytostatic agents such as antiestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene, yodoxifene), progestogens (eg, megestrol acetate), aromatase inhibitors (eg anastrozole, letrazole, vorazole, exemestane) ), antiprogestogens, antiandrogens (for example flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH agonists and antagonists (for example goselerin acetate, luprolide), testosterone 5a-dihydroreductase inhibitors (for example finasteride), anti-invasion agents (for example metalloproteinase inhibitors such as marimastat and inhibitors of the receptor function of activator of plasminogen and urokinase) and inhibitors of the function of the growth factor (such growth factors include, for example, vascular endothelial growth factor, epithelial growth factor, platelet-derived growth factor and hepatocyte growth factor and such inhibitors include antibodies to growth factor, growth factor receptor antibodies, tyrosine kinase inhibitors and serine / threonine kinase inhibitors), - (iii) antiproliferative / antineoplastic drugs and combinations thereof, as used in oncology medical, such as metabolites (for example antifolates such as methotrexate, fluoropyrimidines such as 5-fluorouracil, purine and adenosine analogs, cytosine arabinoside); antitumor antibiotics (for example anthracyclines such as doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin and mithramycin); platinum derivatives (for example cisplatin, carboplatin); alkylating agents (for example nitrogen mustard, melphalan, chlorambucil, busulfan, cyclophosphamide, isophosphamide, nitrosoureas, thiotepa); antimitotic agents (for example vinca alkaloids such as vincristine and taxoids such as taxol, taxotere); topoisomerase inhibitors (for example epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan); (iv) anti-angiogenic agents that work by mechanisms different from those defined in the above (for example tyrosine kinase receptors such as Tie-2, inhibitors of integrin function? 3, angiostatin, razoxin and thalidomide) and that include vascular targeting agents; and (v) differentiation agents (for example retinoic acid and vitamin D). "In accordance with this aspect of the invention, there is provided a pharmaceutical product comprising a compound of the formula (I) as defined above and an additional antitumor substance as defined above for the joint treatment of cancer. of their use in therapeutic medicine, the compounds of formula (I) and their pharmaceutically acceptable salts or in vivo hydrolysable esters or amides thereof are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of cell cycle activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the research in search of new therapeutic agents. pharmaceutical composition comprising a compound of formula (I), or the use of a compound of formula (I), as a medicament to, or the use of a compound of formula (I) in a method of treatment or the use of a compound of formula (I) in the manufacture of a medicament or the use of a compound of formula (I) in the treatment of Cancer, as described herein, it should be understood that therein, the definition of the compound of formula (I) includes the compounds: N- (2-amino-6-hydroxyphenyl) -4- (1-methylhomopiperazine-4- il) benzamide; N- (2-amino-6-methyl-phenyl) -4- (1-methylhomopiperazin-4-yl) benzamide; N- (2-Aminophenyl) -4- (1-tert-butoxycarbonyl-homopiperazin-4-yl) -benzamide; and N- (2-aminophenyl) -4- (1-methylhomopiperazin-4-yl) benzamide. The invention will now be illustrated in the following examples in which, generally: (i) the operations are carried out at room temperature, that is, in the range of 17 to 25 ° C and under an inert gas atmosphere such as argon, unless otherwise stated; (ii) the evaporations are carried out by rotary vacuum evaporation and treatment processes which are carried out after the separation of the residual solids by filtration; (iii) column chromatography (by the instantaneous process) and medium pressure liquid chromatography (MPLC) are performed on silica Merck Kieselgel (Art. 9385) or Merck Lichoprep RP-18 (Art. 9303), reverse phase silica obtained from E. Merck, Darmstadt, Germany or high pressure liquid chromatography (HPLC) is carried out on C18 reversed phase silica, for example on a preparative reversed phase Dynamax C-18 60A column; -. { -i-v -) - yields, when they are present, are not necessarily the maximum available; (v) in general, the structures of the final products of formula (I) are confirmed by nuclear magnetic resonance (MR) and / or mass spectrum techniques; Rapid atomic bombardment (BAR) mass spectrum data are obtained using a Platform spectrometer and, when appropriate, positive ion data or negative ion data are collected; the NMR chemical shift values are measured on the delta scale [the proton magnetic resonance spectra are determined using a Jeol JNM EX 400 spectrometer with a field strength of 400 MHz, a Varian Gemini 2000 spectrometer operating at a field strength 300 MHz or a Bruker AM300 spectrometer operating with a field strength of 300 MHz]; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; c, quartet; m, multiplet; a, broad; (vi) intermediates are usually not fully characterized and purity is determined by thin layer chromatography, HPLC, infrared (IR) and / or NMR analysis; (vii) the melting points are uncorrected and are determined using a Metler SP62 automatic melting point apparatus or an oil bath apparatus; the melting points for the final products of the formula (I) are determined after crystallization from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or mixed; (viii) the following abbreviations have been used: DMF N, N-dimethylformamide DMSO dimethyl sulfoxide THF tetrahydrofuran.
Example 1 N- (2-Aminophenyl) -4-pyridin-4-ylbenzamide. N- (2-tert-butoxycarbonylaminophenyl) -4-pyridin-4-ylbenzamide is stirred at room temperature for about 20 hours (Method 1, 100 mg, 0.26 mmol). ), 2 ml of 1,4-dioxane and a 4M solution of hydrogen chloride in 2 ml of dioxane. The resulting precipitate is collected by filtration and washed with isohexane and diethylether and dried under vacuum to provide the title compound as its hydrochloride (43 mg, 46%); NMR spectrum: (DMSO-d6) 7.31 (m, 2H), 7.39 (t, 1H), 7.54 (t, 1H), 8.17 (d, 2H); 8.30 (d, 2H), 8.40 (d, 2H), 8.96 (d, 2H), 10.62 (s, 1H); Mass spectrum: M + H + 290.
Example 2 - Using a procedure analogous to that described "in Example 1, the starting material N- (2-tert-butoxycarbonylaminophenyl) -benzamide is reacted to provide the compounds described in Table 1. Unless otherwise indicated, Each compound is obtained as its hydrochloride salt.
Note R Analytical data SM quinolin- NMR spectrum: (DMS0-ds) 7.37 Meth 2 8-yl (t, 1H), 7.49, (t, 1H), 7.62 (d, 1H), 7.78 (m, 5H), 7.93 (d, H), 8.18 (d, 1H), 8.31 (d, 2H), 8.72 (d, 1H), 9.04 (dd, 1H), 10.75 (s, 1H); Mass spectrum: M + H + 340 pyridin- NMR spectrum: (D SO-d6) 7.32 Meth 3 3-yl (m, 2H), ~ 7.43 (d, 1H), 7.57 (d, 1H), 7.95 (dd, 1H), 8.03 (d, 2H), 8.27 (d, 2H), 8.72 (d, 1H), 8.83 (d, 1H), 9.25 (s, 1H), 10.60 (s, 1H), Mass spectrum: M + H * 290. pyridin- NMR spectrum: (DMSO-d6): 6.63 Meth 4 2-yl salt (t, 1H), 6.80 (d, 1H) 6.98 acid (t, 1H), 7.23 (d, 1H) 7.44 formic (t, 1H), 7.95 (t, 1H) 8.13 (m, 3H), 8.22 (d, 2H) 8.72 (d, 1H), 9.74 (s, 1H): Mass spectrum: M + H * 290 Note R1 Analytical data SM 4 6- (methoxy) - NMR spectrum: (DMSO-d6) Meth 5 1, 2"pyrazin-3 - ~ 4.09 (s, 3H), 7.32 (m, yl 4H), 7.49 (m, 1H), 8.24 (m, 5H), 10.46 (s, 1H); Mass spectrum: M + H + 321. 5 furan-3-yl NMR spectrum: (DMSO- Meth 6 d6): 7.09 (s, 1H), 7.25 (m, 3H), 7.58 (d, 1H), 7.83 (d, 3H), 8.06 (d, 2H), 8.33 (s, 1H), 10.32 (s, 1H); Mass spectrum: M + H + 279. 6 2- NMR spectrum: (DMSO- Meth 7 methylpyridineds): 2.82 (s) , 3H), 7.21 4-yl (m, 1H), 7.29 (m, 2H), 7.51 (d, 2H), 8.29 (d, 2H), 8.31 (m, 3H), 8.41 (s, 1H), 8.89 (d, 1H), 10.51 (s, 1H); Mass spectrum: M + H + 304. 7 2- NMR spectrum: (DMSO- Meth 8 fluoropyridine-6): 7.26-7.33 (m, 3H), 4- ilo 7.49 (d, 1H), 7.68 (s, 1H), 7.83 (m, 1H), 8.08 (d, 2H), 8.23 (d, 2H), 8.37 (d, 1H), 10.50 (s, 1H) Mass spectrum: M + H + 308.
Note Analytical data SM thiazole-2-NMR spectrum: (D SO-d6) Meth 9 ilo 7.39 t, 1H), 7.48 (t, 1H), 7.56 d, 1H), 7.64 (d, 1H), 7.92 d, 1H), 8.02 (d, 1H), 8.13 d, 2H), 8.27 (d, 2H), 10.77 (s, 1H); Mass spectrum M + H + 296. 2 -amino- NMR spectrum: (DMS0-ds) Meth 10 pyrimidin- 32 2H), 7.41 (m, 1H), 6-yl 57 2H), 8.30 (m, 4H), 51 1H), 10.64 (s, 1H) Mass spectrum: M + H + 306 10 pyrimidin- NMR spectrum: (DMS0-d6): Meth 11 6-yl 7.33 m, 3H), 7.52 (m, 1H), 8.25 m, 3H), 8.40 (d, 2H), 8.95 d, 1H), 9.33 (s, 1H), 10.52 (s, 1H); Mass spectrum M + H + 291. 11 2 -chloro- NMR spectrum: (DMS0-d6): Meth 12 pyrimidine- 7.39 m, 2H), 7.46 (dd, 1H), 6-yl 7.58 dd, 1H), 8.30 (m, 3H), 8.39 d, 2H), 8.93 (d, 1H), 10.72 (s, 1H), Mass spectrum M + H + 325.
EXAMPLE 3 N- (2-Amino-phenyl) -4-morpholinobenzamide A solution of 1- (N-terbutoxycarbonylamino) -2-aminobenzene (Method 17, 104 mg, 0.5 mmol) in 1.6 ml of DMF is added to 4-morpholinobenzoic acid ( 149 mg, 0.5 mmol) followed by 4- (4,6-dimethoxy-1,3,5-triazinyl-2-yl) -4-methylmorpholinium chloride (method 18, 138 mg, 0.5 mmol) and the reaction is stirred at room temperature for 48 hours. The solvent is removed under vacuum and the resulting residue is partitioned between ethyl acetate and water. The organic phase is separated, then washed with water, brine and dried over sodium sulfate and subsequently filtered. The organic extracts are concentrated in half and a 4M solution of hydrogen chloride in 1 ml of 1 is added., 4-dioxane. The reaction mixture is stirred at room temperature for an additional 64 hours and the resulting precipitate is collected by filtration. This solid is purified by activated HPLC by preparative mass with an increasing gradient of acetonitrile in water (which contains a 5% (v / v) solution of a 1% (v / v) solution of formic acid in methanol) provide the title compound (17 mg, 12%); MR spectrum: (DMSO-d6): 3.25 (m, 4H), 3.76 (m, 4H), 4.83 (s, 2H), 6.60 (m, 1H), 6.79 (dd, 1H), 6.96 (m, 1H) , 7.01 (d, 2H), 7.16 (dd, 1H), 7.90 (d, 2H), 9.31 (broad s, 1H); Mass spectrum: M + H + 298.
Example 4 N- (2-Aminophenyl) -4- (1-methylpiperidin-4-yl) benzamide N- (2-Aminophenyl) -4-piperidin-4-ylbenzamide is stirred (Example 5, 48 mg, 0.16 mmol) and it is dissolved in 2 ml of anhydrous DMF at room temperature. Potassium carbonate (23 mg, 0.16 mmol) is added followed by iodomethane (0.01 ml, 0.16 mmol) and the mixture is stirred for 3 hours. The reaction mixture is diluted with 20 ml of water and extracted with ethyl acetate. The combined extracts are washed once with brine, dried over magnesium sulfate, filtered and the solvent is evaporated to give the title compound as a colorless solid (16 mg, 32%); NMR spectrum: (DMSO-d6): 1.70 (m, 4H), 1.96 (m, 2H), 2.18 (s, 3H), 2.85 (m, 2H), 3.03 (m, 1H), 4.84 (broad, 2H) , 6.57 (m, 1H), 6.76 (d, 1H), 6.95 (m, 1H), 7.16 (d, 1H), 7.36 (d, 2H), 7.99 (d, 2H), 9.54 (broad n, 1H); Mass spectrum: M + H + 310.
Example 5 N- (2-Aminophenyl) -4-piperidin-4-ylbenzamide A 4M solution of hydrogen chloride in dioxane (5 ml, 20 mmol) is added to a stirred solution of N- (2-tert-butoxycarbonylaminophenyl) -4- (1-tert-butoxycarbonyl-piperidine-r-yl) benzamide (method , 693 mg, 1.40 mmol) in 5 mL of 1,4-dioxane and the mixture is stirred at room temperature for 18 hours. The resulting precipitate is filtered and washed with diethyl ether. The resulting solid is dissolved in water and made basic to pH 12 with a 2M aqueous sodium hydroxide solution. The resulting precipitate is filtered, washed with water and dried under vacuum to provide the title compound (338 mg, 82%); MR spectrum: (DMSO-ds): 1.52 (m, 2H), 1.69 (m, 2H), 2.60 (m, 3H), 3.02 (m, 2H), 4.84 (broad, 2H), 6.58 (m, 1H) , 6.76 (d, 1H), 6.95 (m, 1H), 7.16 (d, 1H), 7.43 (d, 2H), 7.89 (d, 2H), 9.53 (broad, 1H) mass spectrum: M + H + 296 .
Example 6 N- (2-aminophenyl) -4- (l-methylpiperazin-4-yl) benzamide N- (2-tert-butoxycarbonylaminophenyl) -4- (l-methylpiperazin-4-yl) benzamide (method 16, 196 mg, 0.48 mmol) is dissolved in a 1M solution of hydrogen chloride in diethylether (7.2 ml, 7.2 mmol) and it is stirred at room temperature for 24 hours. The resulting precipitate is collected by filtration and washed with diethyl ether. To the solid is added 5 ml of a 2M aqueous sodium hydroxide solution and the mixture is extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, filtered and evaporated to give the title compound as a colorless solid (16 mg, 11%), RM spectrum: (CDC13) 2.36 (s, 3H) , 2.57 (t, 4H), 3.33 (t, 4H), 3.88 (broad, 2H), 6.81 (m, 2H), 6.91 (d, 2H), 7.06 (t, 1H), 7.27 (d, 1H), 7.79 (s, 1H), 7.80 (m, 2H), mass spectrum: M + H + 311.
Example 7 N- (2-Aminophenyl) -4- [2- (3-morpholinoaminopropyl) -pyrimidin-6-yl] benzamide N- (2-Aminophenyl) -4- [2- (3-morpholinoaminopropyl) -pyrimidin-6-yl] benzamide trichlorohydrate (method 19.28 mg, 0.52 mmoles) is dissolved in 2 ml of water and becomes basic to pH 10 by the addition of 2 drops of an aqueous solution of 28% ammonium hydroxide. The resulting precipitate is collected by filtration and placed under vacuum at 40 ° C overnight to give the title compound as a yellow solid (9 mg, 40%); NMR (DMSO-d6): 1.75 (m, 2H), 2.37 (m, 6H), 3.41 (broad m, 2H), 3.59 (m, 4H), 4.92 (s, 2H), 6.62 (t, 1H, 6.80 (d, 1H), 6.99 (t, 1H), 7.21 (m, 2H), 7.28 (t, 1H), 8.11 (d, 2H), 8.22 (d, 2H), 8.39 (d, 1H), 9.74 ( s, 1H), mass spectrum: M + H + 433.
EXAMPLE 8 N- (2-Amino-phenyl) -4- [2- (3-morpholinoamino-ethi) ^ pyrimin-6-yl] -benzamide N- (2-aminophenyl) -4- [2- (3-morpholinoaminoethyl) -pyrimidin-6-yl] -benzamide trichlorohydrate (method 24.22 mg, 0.042 mmol) is reacted in a manner analogous to that described for example 7 to provide the title compound as a light yellow solid (12 mg, 68%); MRI (DMS0-d6): 2.45 (m, 4H), 2.54 (m, 2H), 3.51 (m, 2H), 3.59 (m, 4H), 4.92 (s, 2H), 6.62 (t, 1H), 6.80 (d, 1H), 6.99 (t, 1H), 7.07 (t, 1H), 7.20 (d, 1H), 7.24 (d, 1H), 8.11 (d, 2H), 8.23 (d, 2H), 8.40 ( d, 1H), 9.74 (s, 1H); Mass spectrum: M + H + 419.
Example 9 Using an analogous procedure to that described in Example 1, the appropriate starting material, N- (2-tert-butoxycarbonylaminophenyl) benzamide, is reacted to provide the compounds described in Table 2. Unless otherwise indicated, each compound It is obtained as its hydrochloride salt.
Table 2 25 25 Example 10 Using a procedure analogous to that described in Example 1, the appropriate starting material of N- (2-tert-butoxycarbonylaminophenyl) benzamide is reacted to provide the compounds described in Table 3. Unless stated otherwise, it is obtained like its hydrochloride salt.
Table 3 1 3 -pyridyl Spectrum RM: (DMS0-d6): 7.40 Meth (m, 2H), 7.50 (d, 1H), 7.63 44 < d, 1H), 7.91 (t, 1H), 7.99 (t, 1H), 8.18 (m, 2H), 8.58 (d, 1H), 8.89 (d, 1H) (9.10 (s, 1H), 10.76 (s) , 1H); Mass spectrum: M + H + 308.
Example 11 Using an analogous procedure to that described in Example 7, the appropriate starting material of the N- (2-aminophenyl) -benzamide hydrochloride salt is reacted to provide the compounds described in Table 4. Unless established otherwise, each compound is obtained as its free base.
- - Table 4 Note R1 Analytical data SM 1 Mass spectrum: Meth (DMSO-d6) 1.74 (m, 46 2H), 2.42 (broad m, 4H), 3.34 (m, 4H), 3.60 (m, 4H), 4.91 (s, 2H), 6.62 ( t, 2H), 6.81 (m, 3H), 6.99 (t, 1H), 7.20 (d, 1H), 7.79 (d, 2H), 8.09 (m, 3H), 9.72 (s, 1H); Mass spectrum: M + H + 432. 2 Mass spectrum: Meth (DMSO-d6) 3.92 (s, 47 3H), 5.00 (broad, 2H), 6.63 (t, 1H), 6.82 (d, 1H), 7.01 (m, 1H), 7.23 (d, 1H), 8.20 (d, 2H), 8.70 (s, 1H), 8.98 (d, 2H), 9.06 (s, 1H), 9.82 (s, 1H); Mass spectrum: M + H + 345.
Example 12 N- (2-aminophenyl) -4- [5- (piperidin-1-ylmethyl) -l, 3-thiazol-2-yl] benzamide N- (2-tert-butoxycarbonylphenyl) -4- [5- ( piperidin-1-ylmethyl) -1, 3-thiazol-2-yl] benzamide (method 51, 271 mg, 0.54 mmol) in 4 ml of 1,4-dioxane and a 4M solution of hydrogen chloride in 4 ml is added of 1,4-dioxane. The reaction mixture is stirred at room temperature for 17 hours. The resulting precipitate is collected by filtration, washed with diethyl ether and dried in air to provide the title compound as its hydrochloride salt. The crude solid is purified using an Oasis MCX column, eluting with methanol / dichloromethane (0-100%) and then (2M ammonia in methanol) / methanol (0-20%) to give the title compound as its free base (119 mg, 56%); NMR spectrum: (DMSO-d6) 1.40 (m, 2H), 1.50 (m, 4H), 2.41 (m, 4H), 3.74 (s, 2H), 4.94 (s, 2H), 6.61 (t, 1H), 6.80 (d, 1H), 6.99 (t, 1H), 7.18 (d, 1H), 7.80 (s, 1H), 8.06 (d, 2H), 8.09 (d, 2H), 9.78 (s, 1H); Mass spectrum: M + H + 402.
EXAMPLE 13 N- (2-aminophenyl) -4- [2- ( { 3- [2- (dimethylamino) ethoxy] propyl] -amino) pyrimidin-4-yl] benzamide To a solution of dimethylaminoethoxypropropylamine - - (2.02 mg, 12.5 moles) in 125 μ? of, N-dimethylacetamide is added a solution of N- (2-aminophenyl) -4- [2- (methylsulfonyl) pyrimidin-4-yl] benzamide (method 62, 2.2 mg, 5 umoles) in 100 μ? of N, N-dimethylacetamid. The reaction mixture is heated to 50 ° C and stirred for a period of 16 hours, before it is evaporated to dryness to provide the title compound; Mass spectrum: M + H + 435.
Example 14 Using a procedure analogous to that described in example 13, N- (2-aminophenyl) -4- [2- (methylsulfonyl) pyrimidin-4-yl] benzamide (method 62) is reacted with the appropriate amine to provide the compounds described in table 5.
Table 5 - - Example 15 Using a procedure analogous to that described in Example 5, the starting material, N- (2-aminophenyl) benzamide hydrochloride salt is reacted to provide the compounds described in Table 6. Unless stated otherwise, each compound is obtained as its free base.
- - Table 6 EXAMPLE 16 N- (2-aminophenyl) -4-piperazin-1-ylbenzamide To a solution of 4- (4-tert-butoxycarbonyl-piperazin-1-yl) -benzoic acid (1.0 g, 3.3 mmol) -yl (tert-butoxycarbonylamine) 2-a ihobenzene (method 17, 0.68 g, 3.3 mmol) in 10 ml of DF is added 4- (4,6-dimethoxy-1,3,5-riazinyl-2-yl) -4-methylmorpholinium chloride (1.1 g, 4.0 mmoles) (method 18) The mixture is stirred at room temperature for 20 hours.The mixture is concentrated in vacuo and the residue is partitioned between water and ethyl acetate.The organic phase is separated and the aqueous material is extracted again with ethyl acetate The combined organic extracts are dried over magnesium sulfate and evaporated, the residue is purified by flash chromatography (eluting with 4: 1-1: 1 isohexane / ethyl acetate), the product is dissolved in 2.5 ml. of 1,4-dioxane and treated with a 4M solution of hydrogen chloride in 2.5 ml of 1,4-dioxane.The mixture is stirred at room temperature for 4 hours. The resulting liquid is collected by filtration, treated with a 2M aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic extract is dried over magnesium sulfate to give the title compound as a colorless solid (176 mg, 92%); MR spectrum: (DMS0-d6) 2.89 (t, 4H), 3.25 (t, 4H), 4.90 (s, 2H), 6.66 (t, 1H), 6.84 (d, 1H), 7.01 (m, 3H), 7.21 (d, 1H), 7.92 (d, 2H), 9.48 (s, 1H); Mass spectrum: M + H + 297.
- - Example 17 (RS) -N- (2-Aminophenyl) -4-piperidin-3-ylbenzamide To a solution of N- (2-tert-butoxycarbonylaminophenyl) -4-pyridin-3-ylbenzamide (2.0 g, 5.1 mmol) (method 3 in 200 ml of ethanol, 200 mg of Pt02 are added and the resulting mixture is heated to 80 ° C under an atmosphere of hydrogen at 80 Bar for 16 hours. Allow the mixture to cool and filter and evaporate to give (RS) -N- (2-t-butoxycarbonylaminophenyl) -4-piperidin-3-ylbenzamide (1.9 g, 94%). To a solution of (RS) -N- (2-t-butoxycarbonylaminophenyl) -4-piperidin-3-ylbenzamide (1.0 g, 2.5 mmol) in 9.5 ml of 1,4-dioxane is added a solution of hydrogen chloride ( 4M in 1,4-dioxane, 9.5 ml, 38 mmol) and the mixture is stirred at room temperature for 6 hours. The solid that forms is collected by filtration and washed with diethyl ether and dried under vacuum. It is treated with a 2M solution of aqueous sodium hydroxide and extracted three times with ethyl acetate. The combined organic extracts are dried over magnesium sulfate and evaporated to give the product as a colorless solid (0.73 g, 99%); NMR spectrum: (DMSO-d6) 1.71 (m, 4H), 2.61 (m, 2H), 2.75 (m, 1H), 3.03 (m, 2H), 4.92 (s, 2H), 6.64 (t, 1H) , 6.83 (d, 1H), 7.02 (t, 1H), 7.23 (d, 1H), 7.42 (d, 2H), 7.96 (d, 2H), 9.61 (s, 1H); Mass Spectrum: M + H + - - 296.
Example 18 N- (2-aminophenyl) -4- (1, 2, 3, 6-tetrahydropyridin-4-yl) benzamide dihydrochloride stir 4. { 4- [( { 2- [(terbutoxycarbonyl) -amino] phenyl} amino) carbonyl] phenyl} -3,6-dihydropyridin-l (2H) -butylcarboxylate (method 71, 62 mg, 0.13 mmol) and dissolve in 0.4 ml of 1,4-dioxane and add a 4M solution of hydrogen chloride in 0.4 ml. of 1,4-dioxane. The reaction mixture is stirred at room temperature for 24 hours. The resulting precipitate is collected by filtration, washed with diethyl ether and dried under vacuum at 60 ° C to provide the title compound as an off-white solid (34 mg, 89%) .: NMR spectrum: (DMSO-dg) 2.70 (m, 2H), 3.30 (m, 2H), 3.76 (m, 2H), 6.33 (m, 1H), 7.23 (m, 2H), 7.33 (m, 1H), 7.49 (m, 1H), 7.61 (m, d, 2H), 8.10 (d, 2H); 9.27 (s, 1H); Mass Spectrum: M + H + 294. EXAMPLE 19 N- (2-aminophenyl) -4- (1 -. {3, 3- [(2-fluorophenyl) amino] -3-oxopropyl) piperidin-4-yl) benzamide stir N- (2-aminophenyl) -4-piperidin-4-ylbenzamide (Example 5, 162 mg, 0.55 mmol), potassium carbonate (153 mg, 1.1 mmol) and (2-fluorophenyl) -3-bromopropionamide (149 mg , 0.61 mmole) in 5 ml of DNF, at room temperature for approximately 20 hours. The mixture is concentrated in vacuo and the residue is partitioned between water and ethyl acetate. The organic layer is separated, dried over magnesium sulfate and evaporated. The residue is purified by flash chromatography (eluting with 0-25% methanol / dichloromethane) to give the product as a colorless solid (76 mg, 30%).; MR spectrum: (CDC13) 1.92 (m, 4H), 2.18 (m, 1H), 2.57 (t, 2H), 2.64 (m, 2H), 2.72 (t, 2H), 3.19 (d, 2H), 3.62 (s, 2H), 6.80 (m, 2H), 7.05 (m, 4H), 7.31 (d, 1H), 7.34 (d, 2H), 7.87 (d, 2H), 8.08 (s, 1H), 8.44 ( t, 1H), 11.39 (s, 1H); Mass Spectrum: M + H + 461. EXAMPLE 20 4- (L-Acetylpiperidin-4-yl) -N- (2-aminophenyl) benzamide N- (2-aminophenyl) -4-piperidin-4-ylbenzamide is stirred (Example 5.30 mg, 0.10 mmol), and dissolved in 2 ml of N, N-dimethylacetamide and acetic anhydride (0.011 ml, 0.11 mmol) is added. The reaction is stirred at room temperature for 1 hour and then divided between water and ethyl acetate. The organic layer is separated, washed with brine and dried over magnesium sulfate, filtered and evaporated to give the title compound as a colorless solid (23 mg, 68%); NMR spectrum: (DMSO-d6) 1.48 (m, 1H), 1.64 (m, 1H), 1.79 (m, 2H), 2.02 (s, 3H), 2.59 (m, 1H), 2.84 (m, 1H) , 3.13 (m, 1H), 3.92 (d, l! I), 4.53 (d, 1H), 4.85 (s, 2H), 6.58 (m, 1H), 6.76 (d, 1H), 6.95 (m, 1H ), 7.15 (d, 1H), 7.37 (d, 2H), 7.90 (d, 2H), 9.55 (s, 1H): Mass Spectrum: M + H + 338. Example 21 Using a procedure analogous to that described in the example 19, N- (2-aminophenyl) -4-piperidin-4-ylbenzamide (Example 5) is reacted to provide the compounds described in Table 7. Table 7 25 EXAMPLE 22 N- (2-aminophenyl) -4- [1- (4-bromobenzoyl) piperidin-4-yl] benzamide To a solution of -bromobenzoic acid (1.0 g, 3.3 mmol) in 5 ml of DMF is added hexafluorophosphate. benzotriazolyloxytripyrrolidinophosphonium (99 mg, 0.19 mmol) and the mixture is stirred at room temperature for 30 minutes. N- (2-Aminophenyl) -4-piperidin-4-ylbenzamide (Example 5, 50 mg, 0.17 mmol) is added and the mixture is stirred for a further 24 hours. The resulting solution is absorbed on an SCX-2 column, washed with methanol (2"volumes of" column ") and" eluted with a 2M solution of ammonia in methanol (2 column volumes) to provide the product. This is purified by flash chromatography (eluting with 0.20% methanol / dichloromethane) to give the title compound as a colorless solid (29 mg, 18%); NMR spectrum: (DMSO-dg) 1.70 (m, 4H), 2.60 (m, 1H), 2.91 (m, 2H), 3.31 (m, 2H), 4.89 (s, 2H), 6.60 (t, 1H), 6.78 (d, 1H), 6.97 (t, 1H), 7.16 (d, 1H), 7.43 (d, 4H), 7.67 (d, 2H), 7.93 (d, 2H), 9.60 (s, 1H), Mass Spectrum: M + H + 478.
Example 23 Using a procedure analogous to that described in Example 19, (RS) -N- (2-aminophenyl) -4-piperidin-3-ylbenzamide is reacted to provide the compounds described in Table 8.
Table 8 (racemic) Spectrum of CAS no. Mass: M + H + 461 13288- 06-7 J. Prakt. Chem., 1881, 242 02N Mass Spectrum: M + H + 366 (racemic) Mass Spectrum: M + H + 386 (racemic) Mass Spectrum: M + H + 458 (racemic) Mass Spectrum: M + H + 485 0 14 (racemic) Mass Spectrum: M + H + 368 15 (racemic) Mass Spectrum: M + H + 394 Example 24 Using a procedure analogous to that described in Example 19, N- (2-aminophenyl) -4-piperazin-1-ylbenzamide (Example 16) is reacted to provide the compounds described in Table 9.
Table 9 Preparation of the Initial Materials The initial materials for the above examples are commercially available or are easily prepared by standard methods from known materials. For example, the following reactions are illustrations but not limitations of the preparation of some of the initial materials used in the above reactions. Method 1 N- (2-tert-butoxycarbonylaminophenyl) -4-pyridin-4-ylbenzainide. It is stirred at 55 ° C under an argon atmosphere for 96 hours N- (2-tert-butoxycarbonylaminophenyl) -4-bromobenzamide (method 14, 136 mg, 0.33 mmoles), pyridin-4-boronic acid (48 mg, 0.39 mmol), tetraguis (triphenylphosphine) palladium (5 mg, 0.005 mmol), 2 ml of THF and a saturated aqueous solution of 2 ml of sodium hydrogen carbonate. The cooled mixture is partitioned between ethyl acetate and water. The organic fractions are washed with brine, dried over magnesium sulfate, filtered and evaporated to give the title compound (103 mg, 80%), which is used without further purification; Mass Spectrum: M + H + 390. Method 2 N- (2-tert-butoxycarbonylaminophenyl) -4-quinolin-8-ylbenzamide Stir at 80 ° C under an argon atmosphere for 20 hours N- (2-tert-butoxycarbonylaminophenyl) -4- bromobenzamide- (method-14, 200 mg, -0.5 mmol), 8-quinoline boronic acid (104 mg, 0.6 mmol), tetraguis (triphenylphosphine) palladium (8 mg, 0.007 mmol), 3 ml of 1,2-dimethoxyethane and a saturated aqueous solution of 3 ml of sodium acid carbonate. The mixture is allowed to cool before it is partitioned between ethyl acetate and water. The organic fractions are washed with brine, dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by flash column chromatography eluting with methanol / dichloromethane (0-10%) to give the title compound (201 mg, 84%): MR Spectrum: (DMS0-d6): 1.47 (s, 9H ), 7.20 (m, 2H), 7.60 (m, 4H), 7.73 (t, 1H), 7.84 (t, 3H), 8.06 (d, 2H), 8.47 (d, 1H), 8.68 (s, 1H) , 8.93 (m, 1H), 9.91 (s, 1H), Mass Spectrum; M + H + 440. Method 3 N- (2-terbuxycarbonylaminophenyl) -4-pyridin-3-ylbenzamide The title compound is prepared using a procedure analogous to method 2 and used without further purification; Mass Spectrum: M + H + 390.
Method 4 N- (2-tert-butoxycarbonylaminophenyl) -4-pyridin-2-ylbenzamide Stir at 80-85 ° C under an argon atmosphere for 24 hours N- (2-tert-butoxycarbonylaminophenyl) -4- (4,4,5) , 5-tet ame il ~ -T.T37"^ dioxaborolan-2-IlTb ^ ñzaínida (method 13, 132 mg, 0.3 mmol), 2-bromopyridine (40 mg, 0.25 mmol), tetraguis (triphenylphosphine) palladium (4 mg 0.004 mmole), 1.5 ml of 1,2-dimethoxyethane and a saturated aqueous solution of 1.5 ml of sodium hydrogen carbonate, allow the mixture to cool before it is divided between ethyl acetate and water. separate, wash with brine, dry over magnesium sulfate, filter and evaporate to give the title compound (86 mg, 74%) which is used in the next reaction without further purification; Mass Spectrum: M + H + 390 Methods 5-12 Using a procedure analogous to that described in method 4, the starting material N- (2-tert-butoxycarbonylaminophenyl) -4- (4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl) ) benzamide is reacted with the appropriate bromo compound to provide the compounds described in Table 10. When required, the crude residues are purified by flash column chromatography eluting with methanol / dichloromethane (1:10).
Table 10 Method Analytical data SM 6- (methoxy) -1,2- NMR spectrum: Meth 13 pyrazin-3-yl (DMSO-c) 1.44 (s, 9H), 4. 09 (s, 3H), 7.14 (m, 2H), 7. 34 (d, 1H), 7. 57 (t, 2H), 8.09 (d, 2H), 8. 22 (d, 2H), 8. 26 < d, 1 H); Mass Spectrum: M + H 421. Furan-3-yl Mass Spectrum; Meth 13 (M + H + -tBu) 323. -methylpyridin NMR spectrum: Meth 13 4-yl (DMS0-ds) 1.46 (s, 9H), 2.57 (s, 3H), 7.20 (m, 2H), 7.59 ( m, 3H), 7.69 (s, 1H), 7.98 (d, 2H), 8.10 (d, 2H), 8.56 (d, 1H), 8.67 (s, 1H), 9.92 (s, 1H); Mass Spectrum M + H + 404 2 - . 2-fluoropyridin- NMR spectrum: Meth 13 4-yl (DMSO-d6). 1-46 (s, 9H), 7.20 (m, 2H), 7.57 (m, 2H), 7.65 (s, 1H), 7.81 (m, 1H), 8.06 (d, 2H), 8.12 (d, 2H) , 8.37 (d, 1H), 8.68 (s, 1H), 9.94 (s, 1H); Mass Spectrum: (M + H + Boc) 308 thiazolyl-2-yl Mass Spectrum: Meth 13 (M + H + -tBu) 340 10 I 2-aminopyrimidin- Mass Spectrum Meth 13 6-yl (M + Na +) 428 11 Pirimidin-6-yl Mass Spectrum Meth 13 (M + H + -tBu) 335 12 I 2-chloropyrimidin- NMR spectrum: Meth 13 6-yl (DMSO-d6) 1.46 (s, 9H), 7.23 (m , 2H), 7.57 (t, 2H), 8.15 (d, 2H), 8.29 (d, 1H), 8.38 (d, 2H), 8.73 (broad, 1H), 8.91 (d, 1H), 10.00 (s, 1H Mass Spectrum: (M + H + -tBu) 369, Method 13 N- (2-tert-butoxycarbonylaminopheyl) -4- (4,4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) benzamide N- (2-tert-butoxycarbonylamino-phenyl) -4-bromobenzamide is added (method 14) 3.0 g, 7.7 mmoles) to a solution of bis-pinacolato diboron (2.3 g, 9.2 mmol) 1,1-bis (diphenylphosphino) ferrocene dichloropalladium (II) chloride (157 mg, 0.19 mmol) and potassium acetate (2.3 g, 23 tronóles) in 48 ml of DMF at 80 ° C under an argon atmosphere for 20 hours. The mixture is allowed to cool and the solvent is removed in vacuo. The residue is partitioned between ethyl acetate and water. The organic fractions are washed with brine, dried over magnesium sulfate and evaporated to give the title compound (3.9 g, quantitative), which is used without further purification; MR spectrum: (DMS0-d6) 1.14 (s, 6H), 1.31 (s, 9H), 1.43 (s, 6H), 7.16 (m, 2H), 7.52 (m, 2H), 7.79 (d, 2H) 7.95 (d, 2H), 8.66 (s, 1H), 9.86 (s, 1H); Mass Spectrum: (M + H + -Boc) 383.
Method 14 N- (2-tert-butoxycarbonylaminophenyl) -bromobenzamide 4- (4,6-Dimethoxy-1,3,5-triazinyl-2-yl) -4-methylmorpholinium chloride (Method 18; 5.4 g, 19.4 mmol. ) to a solution of 4-bromobenzoic acid (3.5 g, 17.4 mmol) and 1- (N-terbutoxicabonylamino) -2-aminobenzene (method 17, 4.3 g, 20.9 mmol) in 100 ml of DMF and stirred at room temperature for 20 hours. The reaction mixture is divided between water and ethyl acetate. The organic fractions are washed with a saturated aqueous solution of sodium acid carbonate, water, 1M aqueous hydrochloric acid, water and brine, before it is dried over magnesium sulfate. The organic fractions were then evaporated "to give the title compound (7.1 g, quantitative), which is used without further purification. RM spectrum: (DMSO-d6) 1.45 (s, 9H), 7.18 (m , 2H), 7.54 (m, 2H), 7.76 (d, 2H), 7.90 (d, 2H) (8.63 (s, 1H), 9.86 (s, 1H); Mass Spectrum: (M + H + -Boc) 291.
Method 15 N- (2-tertbutoxycarbonylaminophenyl) -4- (1-tert-butoxycarbonylpiperidin-4-yl) benzide 1- (N-1-butoxycarbonylamino) -2-aminobenzene (method 17, 3.1 g, 14.7 mmol) is added to a stirred solution of 4- (l-tert-butoxycarbonylpiperidin-4-yl) benzoic acid (4.1 g, 13.4 mmol) in 50 ml of DMF and the mixture is stirred at room temperature for 10 minutes. 4- (4,6-Dimethoxy-1,3,5-triazinyl-2-yl) -4-methylmorpholinium chloride (method 18, 4.45 g, 16.1 mmol) is added and the mixture is stirred at room temperature for 24 hours . The solvent is evaporated and the residue is dissolved in 100 ml of ethyl acetate and washed with water. The organic fractions are dried over magnesium sulfate, filtered and evaporated. The resulting gum is purified by flash chromatography using 1% methanol / dichloromethane to provide the title compound as a foam (5.44 g, 82%); NMR spectrum: (DMSO-d6) 1.41 (s, 9H), 1.43 (s, 9H), 1.54 (m, 2H), 1.77 (m, 2H), 2.79 (m, 3H) (4.08 (m, 2H) , 7. 15 (m, 2H), 7.40 (d, 2H), 7.52 (m, 2H), 7.87 (d, 2H), 8. 60 (broad, 1H), 9.74 (broad, 1H), Mass Spectrum: (M + H + -Boc) 396. Method 16 N- (2-tert-butoxycarbonylaminophenyl) -4- (l-methylpiperazin-4-yl) benzamide They dissolve 4- (l-methyl-piperazin-4-yl) benzoic acid (250 mg, 1.13 mmol) and 1- (N-terburoxycarbonylamino) -2-aminobenzene (method 17, 331 mg, 1.59 mmol) in 3 ml of DMF. 4- (4,6-Dimethoxy-1,3,5-triazinyl-2-yl) -4-methylmorpholinium chloride (method 18, 313 mg, 1.13 mmol) is added and the resulting solution is stirred for 20 hours at room temperature. ambient. The solution is poured into water and extracted several times with ethyl acetate. The combined organic extracts are dried over magnesium sulfate and evaporated. The residue is purified by flash chromatography (eluting with 99: 1-> 9: 1 dichloromethane: methanol) to give the title compound as a colorless gum which crystallizes by trituration (240 mg, 52%): Mass Spectrum: M + H + 411.
Method 17 1- (N-tert-butoxycarbonylamino) -2-aminobenzene The title compound is prepared according to the method in the literature described-in-Seto, C,? Mathias, J.P .; Whitesides, G. M.; J. Am. Chem. Soc, 1993, 115, 1321-1329.
Method 18 Chloride of 4- (4,6-dimethoxy-1,3,5-triazinyl-2-yl) -4-methylmorpholinium Chloride of 4- (4,6-dimethoxy-1,3,5-triazinyl) is prepared 2-yl) -4-methylmorpholinium according to the procedure in the literature described in Kunishima,. , Kawachi, C, orita, J., Terao, K., I asaki, F., Tani, S., Tetrahedron, 1999, 55, 13159-13170.
Method 19 N- (2-aminophenyl) -4- [2- (3-morpholinoaminopropyl) -pyrimidin-6-yl] benzamide trichlorohydrate N- (2-tertbutoxyminophenyl) -4 - [2- (3-morpholinoaminopropyl) is suspended -pyrimidin-6-yl] -enoxamide (method 20, 64 mg, 0.120 mmol) in 1.5 ml of 1,4-dioxane and a 4M solution of hydrogen chloride in 1 ml of 1,4-dioxane is added. The reaction mixture is stirred at room temperature for 64 hours. The reaction mixture is diluted with diethyl ether and the resulting precipitate is collected by filtration, washed with diethyl ether and dried in air, to give the title compound (as its hydrochloride salt) as an off-white solid (6-2 mg. , 95%) -: Mass Spectrum: M + H + 433.
Method 20 N- (2-tertbutoxyminophenyl) -4- [2- (3-morpholinoaiinopropyl) -pyrimidin-6-yl) benzamide N- (2-tertbutoxyminophenyl) -4- (2-methylsulfonylpyrimidin-6-yl) benzamide is dissolved (method 21, 62.5 mg, 0.133 mmol) in a mixture of 2 ml of THF and 2 ml of N, N-dimethylacetamide and N- (3-aminopropyl) morpholine (60 μ ?, 0.411 mmol) is added. The reaction mixture is heated to 50 ° C and stirred for 2 hours. The reaction mixture is then cooled and the solvents are removed under reduced pressure. The resulting oil is purified by elution through silica with 5% methanol in dichloromethane to provide the title compound as a colorless solid (65 mg, 92%); NMR spectrum: (DMSO-d6) 1.45 (s, 9H), 1.74 (m, 2H), 2.37 (m, 6H), 3.40 (broad, 2H), 3.59 (m, 4H), 7.20 (m, 2H) , 7.23 (d, 1H), 7.34 (t, 1H), 7.57 (d, 1H), 8.08 (d, 2H), 8.26 (d, 2H), 8.40 (m, 1H), 8.72 (s, 1H), 9.94 (s, 1H); Mass Spectrum: M + H + 534.
Method 21 N- (2-tertbutoxyminophenyl) -4- (2-methyl-sulfonyl-pyrimidin-6-yl) -benzamide N- (2-terbutoxy-phenyl-phenyl) -4- (2-thiomethylpyrimidin-6-yl) -benzamide is dissolved (method 22, 140 mg , 0.32 mmol) in 8 ml of methanol and a small amount of ethyl acetate, followed by a solution of Oxonem (630 mg, 1.02 mmol) in 4 ml of water. The resulting suspension is stirred at room temperature for 1 hour before it is partitioned between ethyl acetate and a mixture of water and saturated sodium bicarbonate. The organic phase is separated and the aqueous phase is extracted with additional aliquots of ethyl acetate. The combined organic extracts are washed with brine and dried over magnesium sulfate. Evaporation to dryness affords the title compound as a whitish powder (126 mg, 84%); NMR spectrum: (DMSO-d6) 1.45 (s, 9H), 3.54 (s, 3H), 7.20 (m, 2H), 7.57 (t, 2H), 8.18 (d, 2H), 8.48 (d, 2H) , 8.54 (s, 1H), 8.73 (s, 1H), 9.20 (d, 1H), 10.02 (s, 1H); Mass Spectrum: (M + H + -Boc) 369.
Method 22 N- (2-terbutoxyminophenyl) -4- (2-thiomethylpyrimidin-6-yl) benzamide 4-iodo-2-methylthiopyrimidine (method 23, 360 mg, 1.43 mmol) is reacted with N- (2-terbutoxycarbonylaminophenyl) -4- (4,4,5, 5-tetramethyl-l, 3,2-dioxaborolan-2-yl) benzamide (method 13, 631 mg, 1.44 mmo) -in 1-way-analogous to 1-a described in method 4 to provide the crude title compound. This is purified by elution through silica with a solution of ethyl acetate in isohexane (25% to 50% (v / v)) to give the pure title compound as a light yellow foam (306 mg, 49%); NMR spectrum: (DMS0-d6) 1.45 (s, 9H), 2.63 (s, 3H), 7.20 (m, 2H), 7.57 (t, 2H), 7.91 (d, 1H), 8.13 (d, 2H) , 8.37 (d, 2H), 8.72 (s, 1H), 8.77 (d, 1H), 9.97 (s, 1H), Mass Spectrum: (M + H + -tBu) 381.
Method 23 4-Iodo-2-methylthiopyrimidine 4-Chloro-2-methylthiopyrimidine (5 g, 31.15 mmol) is added dropwise to a cooled solution (0 ° C) of 57% aqueous hydroiodic acid. Stirring is continued at 0 ° C for 30 minutes, before heating to room temperature and stirring for 24 hours. Aqueous sodium bicarbonate is then added cautiously and the resulting suspension is made basic until pH 9 by the addition of sodium carbonate. The mixture is extracted with ethyl acetate and the extracts are dried over magnesium sulfate and concentrated by reduced pressure. The resulting solid is dissolved in boiling isohexane and cooled by cooling overnight.
The resulting solid is filtered and dried to provide the title compound as the colorless needles (5.4 g, 69%); NMR spectrum: (CDC13) 2.55 (s, 3H), 7.40 (d, 1H), 7.98 (d, 1H); Mass Spectrum: M + H + 253.
Method 24 N- (2-aminophenyl) -4- [2- (3-morpholinoaminoethyl) -pyrimidin-6-yl] benzamide trichlorohydrate N- (2-terbutoxyminophenyl) -4- [2- (3-morpholinoaminoethyl) is reacted ) -pyrimidin-6-yl] benzamide (method 25, 59 mg, 0.113 mmol) in a manner analogous to that described for method 19 to provide the title compound (as its hydrochloride salt) as a beige solid (56 mg, 94%); Mass Spectrum: M + H + 419.
Method 25 N- (2-tertbutoxyminophenyl) -4- [2- (3-morpholinoaminoethyl) -pyrimidin-6-yl] benzamide N- (2-butoxyminophenyl) -4- (2-methylsulfonylpyrimidin-6-yl) is reacted benzamide (method 21, 62.5 mg, 0.133 mmol) with N- (2-aminoethyl) morpholine (60 μ ?, 0.457 mmol) in a manner analogous to that described in method 20 to afford the title compound as a light yellow solid (66 mg, 96%); NMR spectrum: (DMS0-d6) 1.46 (s, 9H), 2.45 (broad m, 4H), 3.30 (m, 2H), 3.50 (broad m, 2H), 3.58 (m, 4H), 7.14 (t, 1H), 7.17 (m, 1H), 7.22 (m, 1H), 7.25 (d, 1H), 7.57 (d, 2H) 8-O9 (d, 2H), 8.27 (d, 2H), 8.42 (d, 1H), 8.73 (s, 1H), 9.94 (s, 1H); Mass Spectrum: M + H + 519.
Method 29 N- (2-terbutoxycarbonylaminophenyl) -4-. { 2- [(3-piperidin-ylpropyl) amino] pyrimidin-4-yl} benzamide to a tube Pyrex 24 tran x 150 mm, charged with 3-aminopropylpiperidine (73 mg, 0.51 mmol) is added a solution of N- (2-tert-butoxycarbonylaminophenyl) -4- (2-chloropyrimidin-4-yl) benzamide (method 52, 85 mg, 0.20 mmol) in 4.6 ml of?,? - dimethylacetamide The reaction mixture is then heated to 50 ° C and stirred for 16 hours before it is evaporated to dryness The resulting residue is purified by flash chromatography on 10 g of silica eluting with methanol / dichloromethane (5-15%) to provide the title compound (48 mg, 45%). Mass Spectrum: M + H + 531.
Methods 30-36 Using a procedure analogous to that described in method 29, the starting material N- (2-tert-butoxycarbonylaminophenyl) -4- (2-chloropyrimidin-4-yl) benzamide (method 52) is reacted with the appropriate amine for Provide the compounds described in Table 11. When required, the crude residues are purified by flash column chromatography on 10 g of silica eluting with methanol / dichloromethane (5-15%).
Table 11 Method R Analytical data SM 30 Mass Spectrum: M + H + 514. 31 Mass Spectrum: M + H + 546. 32 Mass Spectrum: M + H + 533. 33 Mass Spectrum: M + H + 505 Method 37 N- (2-tert-butoxycarbonylaminophenyl) -4- [2- (3-morpholiri-4-ylpropoxy) iridi-4-yl] benzamide To a suspension of sodium hydride in 1 ml of tetrahydrofuran are added dropwise, syringe a solution of 3-N-morpholinopropanol (147 mg, 1.01 mmol). The reaction mixture is stirred under an argon atmosphere for 30 minutes, and then added, by means of a cannula, to a solution of N- (2-terbutoxycarbonylaminophenyl) -2-fluoropyridin-4-ylbenzamide (method 8, 119 mg, 0.29 mmoles) in 2 ml of tetrahydrofuran. The mixture is then stirred under an argon atmosphere for 2 hours at room temperature before it is heated to 50 ° C and stirred for an additional 5.5 hours. The reaction mixture is allowed to - Cool before it is divided between ethyl acetate and water. The organic fractions are separated and the aqueous fraction is further extracted with ethyl acetate. The combined organic layers are then combined, washed with brine, dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by flash chromatography on 20 g of silica, eluting with methanol / dichloromethane (0-10%) to give the title compound (70 mg, 45%); NMR spectrum: (DMSO-d6) 1.46 (s, 9H), 1.92 (m, 2H), 2.38 (m, 4H), 2.45 (m, 2H), 3.59 (t, 4H), 4.36 (t, 2H) , 7.20 (m, 3H), 7.39 (dd, 1H), 7.57 (d, 2H), 7.97 (d, 2H), 8.08 (d, 2H), 8.26 (d, 1H), 8.67 (s, 1H), 9.91 (s, 1H); Mass Spectrum: M + H + 533.
Method 38 N- (2-tert-butoxycarbonylaminophenyl) -4- (6-methylpyridin-3-yl) benzamide Using an analogous procedure to that described in method 4, N- (2-terbutoxycarbonylaminophenyl) -4- (4.4 , 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) benzamide (method 13, 1.20 g, 2.74 mmol) with 2-methyl-5-bromopyridine (505 mg, 2.94 mmol). The crude residue is purified by flash chromatography on 90 g of silica eluting with ethyl acetate / isohexane (40-100%) to give the title compound. (504 mg, 46%); MR spectrum: ... (DMSO-de) 1.46 (3, 9H), 2.51 (s, 3H), 7.19 (m, 2H), 7.40 (d, 1H), 7.58 (ra, 2H), 7.91 (d, 2H), 8.08 (d, 3H), 8.66 ( s, 1H), 8.86 (d, 1H), 9.89 (s, 1H); Mass Spectrum: M + H + 404.
Method 39 N- (2-tert-butoxycarbonylaminophenyl) -4-. { 2- [(3-piperidin-1-ylpropyl) amino] thieno [3,2-d] pyridimin-4-yl} benzamide A solution of 3-aminopropylpiperidine (60 μ ?, 0. 38 mmoles) and N- (2-tert-butoxycarbonylaminophenyl) -4- [2- (methylsulfonyl) thieno [3,2- d] pyrimidin-4-yl] benzamide (method 54, 81 mg, 0.15 mmole) in N, N- dimethylacetamide is heated first at 50 ° C for 23 hours and then further heated to 75 ° C over a period of 16 hours. The reaction mixture is evaporated to dryness and the crude residue is purified by flash chromatography on 10 g of silica, eluting with methanol / dichloromethane (0-15%) to give the title compound (23 mg, 26%); Mass Spectrum: M + H + 587.
Method 40 N- (2-tert-butoxycarbonylamino-4-enyl) -4- (thieno [3,2-d] pyrimidin-4-ylbenzamide) Using an analogous procedure to that described in method 4, 4-chlorothieno is reacted [3, 2 - d] pyrimidine (538 mg, 3.15 mmol) with N- (2-tert-butoxycarbonylaminophenyl) -4- (4,4,5, 5-tetramethyl-l, 3,2-dioxaborolan-2-yl) benzamide '(method 13, 1.53 g, 3.50 mmol) The crude residue is purified by flash chromatography on silica eluting with ethyl acetate / hexane (25-75%) to give the title compound (1.08 g, 69%); NMR spectrum: (DMS0 -d6) 1.47 (s, 9H), 7.21 (m, 2H), 7.57 (t, 2H), 7.79 (d, 1H), 8.23 (d, 2H), 8.34 (d, 2H), 8.64 (d, 1H) ), 8.75 (s, 1H), 9.35 (s, 1H), 10.03 (s, 1H); Mass Spectrum: M + H + 447.
Method 41 N- (2-aminophenyl) -4-. { 2- [(3-piperidin-1-ylpropyl) amino] irimidin-5-yl} benzamide To a solution of N- (2-tert-butoxycarbonylaminophenyl) -4- (2-chloropyrimidin-5-yl) benzamide (method 53, 80 mg, 0.19 mmol) in 3.5 ml of N, -dimethylacetamide is added 3-aminopropylpiperidine (108 mg, 0.76 mmol). The reaction mixture is stirred at 50 ° C for 20 hours before it is allowed to cool. The reaction mixture is divided between water and ethyl acetate, before it is filtered by gravity through a column of diatomaceous earth Varian Chem Elut (CE1010). The resulting solution is then concentrated under reduced pressure and purified by flash column chromatography eluting with methanol / dichloromethane (0-20%) to provide the title compound, which is used without further purification; Mass Spectrum: M + H + 531.
Methods 42-43 Using a procedure analogous to that described in method 41, N- (2-tert-butoxycarbonylaminophenyl) -4- (2-chloropyrimidin-5-yl) benzamide (method 53) is reacted with the appropriate amine to provide the compounds described in Table 12. When required, the crude residues are purified by flash column chromatography on 10 g of silica eluting with methanol / dichloromethane (0.20%).
Table 12 Method 44 N- (2-tert-butoxycarbonylaminophenyl) -3-fluoro-4-pyridin-3-ylbenzamide. It is stirred at 80 ° C under an argon atmosphere for 48 hours 2 - [(4-bromo-3-fluorobenzoyl) amino] phenylcarbamate of terbutyl (method 63, 205 mg, 0.5 min), 3-pyridinboronic acid (74 mg, 0.6 mmol), tetraqruis (triphenylphosphine) palladium (104 mg, 0.09 mmol), 3 ml of 1,2-dimethoxyethane and 3 ml of a saturated aqueous solution of sodium hydrogen carbonate. The cooled mixture is partitioned between ethyl acetate and water. The aqueous layer is separated using a Varian Chem Elut column (CE1010) and the resulting solution is then concentrated under reduced pressure and purified by flash column chromatography, eluting with ethyl acetate / isohexane (25-75%) to give the compound of the title (186 mg, 91%) Mass Spectrum: M + H + 408.
Method 45 N- (2-tert-butoxycarbonylaminophenyl) -4- [2- (2-pyrrolidin-1-ylethoxy) pyrimidin-5-yl] benzamide Using an analogous procedure to that described in method 44, N- (2-) is reacted terbutoxycarbonylaminophenyl) -4- (4,4,5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) benzamide (method 13, 219 mg, 0.5 mmol) with 5-bromo-2- (2-pyrrolidine -l-iletoxy) pyrimidine (method 64, 136 mg, 0.5 mmol) to provide the title compound (71 mg, 28%). Mass Spectrum: M + H + 504.
Method 46-50 Using an analogous procedure to that described in Example 1, the appropriate starting material N- (2-tert-butoxycarbonylaminophenyl) benzamide is reacted to provide the compounds described in Table 13, as their hydrochloride salt.
Table 13 Method 51 N- (2-tert-butoxycarbonylaminophenyl) -4- [5- (piperidin-1-ylmethyl) -1, 3-thiazol-2-yl] benzamide Using an analogous procedure to that described in method 44, N- is reacted (2-tert-butoxycarbonylaminophenyl) -4- (4, 4, 5, 5-tetramethyl-1,2-dioxaborolan-2-yl) benzamide (method 13, 219 mg, 0.5 mmol) with 1- [(2-chloro -l, 3-thiazol-5-yl) methyl] piperidine (108 mg, 0.5 mmol) to provide the title compound (271 mg> 100%), which is carried to the next step; Mass Spectrum: M + H + 493.
Method 52 N- (2-tert-butoxycarbonylaminophenyl) -4- (2-chloropyrimidin-4-yl) benzamide Using an analogous procedure to that described in method 4, N- (2-tert-butoxycarbonylaminophenyl) -4- (4,, 5, 5-etramethyl-1, 3,2-dioxaborolan-2-yl) benzamide (method 13, 3.9 mg, 8.9 mmol) with 2,4-dichloropyrimidine (3.06 mg, 20.5 mmol). The pure residue is purified by flash chromatography on silica eluted with ethyl acetate / isohexane (1: 1) to give the title compound (1.2 g, 32%); MR spectrum: (DMS0-d6) 1.45 (s, 9H), 7.23 (m, 2H), 7.57 (t, 2H), 8.15 (d, 2H), 8.29 (d, 1H), 8.38 (d, 2H) 8.73 (s, 1H), 8.91 (d, 1H); 10.00 (s, 1H); Mass Spectrum: M-H " 423 ' Method 53 N- (2-tert-butoxycarbonylaminophenyl) -4- (2-chloropyrimidin-5-yl) benzamide. It is stirred at 80 ° C under an argon atmosphere for 18 hours. N- (2-tert-butoxycarbonylaminophenyl) -4- (4,4) , '5, 5-tetramethyl -1, 3, 2-dioxaborolan-2-yl) benzamide (method 13, 4.0 g, 9.12 mmol), 5-bromo-2-chloropyrimidine (1.76 g, 9.12 mmol), tetrakis (triphenylphosphine) ) aladium (527 mg, 0.46 mmol), 40 ml of 1,2-dimethoxyethane and a saturated aqueous solution of 40 ml of sodium hydrogen carbonate. The cooled mixture is concentrated under reduced pressure. The residue is then stirred with ethyl acetate for 1 hour and the resulting solid is collected by suction filtration and dried to provide the title compound (2.38 g, 61%); NMR spectrum: (DMSO-d6) 1.47 (s, 9H), 7.20 (m, 2H), 7.58 (d, 2H), 8.02 (d, 2H), 8.11 (d, 2H), 8.66 (s, 1H) , 9.23 (s, 1H), 10.93 (s, 1H); Mass Spectrum: M + H + - cBu 369.
Method 54 N- (2- tert-butoxycarbonylaminophenyl) -4- [2- (methylsulfonyl) thieno [3,2- d] pyrimidin-4-yl] benzamide - - To a solution cooled to 0 ° C of N- (2-tert-butoxycarbonylaminophenyl) -4- [2 - (methyl] thieno [3,2-d] pyrimidin-4-yl] benzamide (method 55, 960 mg, 1.95 mg ) in 40 ml of DMF, meta-chloroperbenzoic acid (57%, 630 mg, 2.08 mmol) is added and the reaction mixture is stirred, allowing it to warm to room temperature. After 3 hours an additional portion of meta-chloroperbenzoic acid (70%, 589 mg, 2.40 mmol) is added and stirring is continued for 2 hours. The reaction mixture is then carefully poured into an aqueous solution of sodium metabisulfite (0.25M, 100 ml) before the addition of 100 ml of ethyl acetate. The insoluble material is separated by filtration and dried under vacuum to provide the title compound (586 mg, 57%); NMR spectrum: (DMS0-d6) 1.46 (s, 9H), 3.57 (s, 3H), 7.18 (t, 1H), 7.24 (t, 1H), 7.59 (m, 2H), 8.00 (d, 1H) , 8.27 (d, 2H), 8.41 (d, 2H), 8.75 (s, 1H), 8.90 (d, 1H), 10.07 (s, 1H); Mass Spectrum: M + Na + 547.
Method 55-59 Using a procedure analogous to that described in method 4, N- (2-tert-butoxycarbonylaminophenyl) -4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) is reacted ) benzamide (method 13) with the appropriate halide to provide the compounds described in Table 14. Where appropriate, the compounds are filtered from the post-division reaction mixtures, or if required, the crude residues are purified by flash column chromatography on silica eluting with methanol / dichloromethane (0.20%).
Table 14 - - Method 60 N- (2-tert.but.-tert.-arbonylaminophenyl) -4- [2- (4-methylpiperazin-1-yl) pyrimidin-4-yl] benzamide Using an analogous procedure to that described in method 41, the N- (2-tert-butoxycarbonylaminophenyl) -4- (2-chloropyrimidin-4-yl) benzamide (method 52.59 mg, 0.14 mmol) with 1-methylpiperazine (77 mg, 0.60 mmol) and the residue is purified by flash chromatography eluting with methanol / dichloromethane (0.20%) to provide the title compound (48 mg, 71%); Mass Spectrum: M + H + 489.
Method 61 4-iodo-N- (3-morpholin-4-ylpropyl) pyridine-2-airiine A solution of 4-iodo-2-fluoropyridine (2.32 mg, 10.00 mmol) and N- (3-aminopropyl) morpholine (4.2 mi, 26.00 mmoles) in 30 ml of N, N-dimethylacetamide is heated at 100 ° C for 20 hours before it is concentrated in vacuo to provide the crude title compound which is used without any further purification; Mass Spectrum: M + H + 348.
Method 62 N-2-aaiinophenyl) -4- [2- (methyl-thio-phenyl) -pyrimidin-4-yl] -benzamide Using an analogous procedure to that described in example 1, N- (2-tert-butoxycarbonylaminophenyl) -4- is reacted [2- (Methylsulfonyl) -pyrimidine-4-yl] banzamide (method 21, 1097 g, 2.34 mmol) to provide the title compound as its hydrochloride salt (1.01 g, 98%); RM Spectrum: (DMSO-ds) ) 3.53 (s, 3H), 7.31 (m, 3H), 7.52 (d, 1H), 8.30 (d, 2H), 8.48 (d, 2H), 8.53 (d, 1H), 9.20 (d, 1H), 10.56 (s, 1H); Mass Spectrum: M + H + 369.
Method 63 2- [(4-Bromo-3-fluorobenzoyl) amino] phenylcarbamate tert-butyl 1- (N-tert-butoxycarbonylamino) -2-aminobenzene is reacted (Method 17, 1.25 g, 6 mmol) with 4-bromo-3 acid -fluorobenzoic acid (1.1 g, 5.0 mmol) in a manner analogous to that described in Method 16 to provide the title compound, which is used without further purification; Mass spectrum: (M + H + -Boc) 311.
Method 64 5-bromo-2 - (2-pyrrolidin-1-ylethoxy) pyrimidine To a solution of? -2-hydroxyethyl pyrrolidine (0.9 ml, 7.71 mmol) and 5-bromo-2-chloropyrimidine (1.2 g, 6.20 mmol), in 7 mL of DMF, sodium hydride (60% en._a.c_ei £ .e ~ mineral, -0.35, 8.75 mmol) is added. - Leaf - mixture is stirred under argon at room temperature for 1 hour before it is heated to '90 ° C and stirred for an additional 1 hour. The reaction mixture is then partitioned between ethyl acetate and water. The organic fractions are separated, dried over magnesium sulfate and evaporated to dryness. The resulting oil is purified by flash chromatography on silica eluting with an increasing gradient of methanol in dichloromethane (which contains a 1% aqueous ammonia solution, 0.88 M) to provide the title compound (640 mg, 38%); Mass spectrum: (CDC13) 1.76 (m, 4H), 2.39 (m, 4H), 3.90 (t, 2H), 4.48 (t, 2H), 8.50 (s, 2H); Mass spectrum: M + H * 272.
Methods 65-66 Using a procedure analogous to that described in Method 39, N- (2-tert-butoxycarbonylaminophenyl) -4- [2- (methylsulfonyl) thieno [3,2- d] pyrimidin-4-yl] benzamide is reacted ( Method 54) with the appropriate amine to provide the compounds described in Table 15. When required, the resulting residues are purified by flash chromatography on silica gel eluting with methanol / dichloromethane (0-15%).
- - Method 67 [2- (4-. {[[2- (2-butoxycarbonylaminophenyl) amino] carbonyl] phenyl) -1,3-thiazol-5-yl] methyl] cyclohexylcarbamate Using an analogous procedure to that described in Method 4, N- (2-tert-butoxycarbonylaminophenyl) -4 - (4,4,5,5-tetramethyl-1,2-dioxaborolan-2-yl) benzamide is reacted (Method 13, 219 mg, -0.5 mmol) with cyclohexylcarbamate of (2-chloro-l, 3-thiazol-5-yl) methyl (138 mg, 0.5 mraoles). The crude residue is stirred in ethyl acetate for 16 hours before it is filtered, mixed with water and the aqueous phase is separated using a Varian Chem Elut column (CE1010). The resulting solution is concentrated and purified by flash chromatography on silica, eluting with methanol / dichloromethane (0-30%) to provide the title compound; Mass spectrum: M + H + 551.
Method 68 N- (2-terbutoxycarbonylaminophenyl) -4-. { 5- [2- (Methylthio) pyrimidin- -ill tien-2-yl} benzamide Using a procedure analogous to that described in Method 4, N- (2-tert-butoxycarbonylaminophenyl) -4- (4,4,5, 5-tetramethyl-1,2,2-dioxaborolan-2-yl) benzamide is reacted ( Method 13, 219 mg, 0.5 mmol) with 4- (5-bromothien-2-yl) -2- (methylthio) irimidine (145 mg, 0.5 mmol). The crude residue is stirred in ethyl acetate / water for 1 hour before it is filtered and the aqueous phase is separated using a Varian Chem Elut column (CE1010). The resulting solution is concentrated and recrystallized from methanol to give the title compound; Mass spectrum: M + H + Boc 463.
Method 69 [2- (4. {[[2-terbutoxycarbonylaminophenyl) -amino] carbonyl phenyl carbamate} phenyl) -1,3-thiazol-5-yl] methyl Using an analogous procedure to that described in Method 4, N- (2-tert-butoxycarbonylaminophenyl) -4- (4,, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) benzamide (Method 13, 219 mg, 0.5 mmol) with (2-chloro-l, 3-thiazol-5-yl) methyl N-phenylcarbamate (136 mg, 0.5 mmol). The crude residue is stirred in ethyl acetate / water for 16 hours before it is filtered and the aqueous phase is separated using a Varian Chem Elut column (CE1010). The resulting solution is concentrated and purified by flash chromatography on silica, eluting with methanol / dichloromethane (0-30%) to give the title compound: Mass spectrum: M + H + -Boc 489.
Method 70 [2- (4-. {[[(2-aminophenyl) amino] carbonyl, phenyl) -1,3-thiazol-5-yl] methyl] -carboylcarbamate Using an analogous procedure to that described in Example 12, The appropriate starting material, N- (2-terbutoxycarbonylaminophenyl) benzamide, is reacted to provide the compound described in Table 16, as its hydrochloride salt.
Table 16 Method 71 -. { 4- [( { 2- [(terbutoxicarbonyl) amino] phenyl} amino) carbonyl] -phenyl} -3,6-dihydropyridine-l (2H) -tertbutylcarboxylate A saturated solution of 3 ml of sodium acid carbonate is added to a stirred solution of 4-. { [(trifluoromethyl) sulfonyl] oxy} 3,6-dihydropyridin-1 (2H) -carboxylate (Method 72, 200 mg, 0.60 mmol) in 3 ml of 1,2-dimethoxyethane. N- (2-tert-butoxycarbonylaminophenyl) -4- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) benzamide (Method 13) (318 mg, 0.72 mmol) is added followed by tetrakis (triphenylphosphine) palladium (100 mg, 0.09 mmol) and the mixture is stirred at 80 ° C for 18 hours. The mixed mixture is divided between ethyl acetate and water. The organic phase is separated and then washed with water and dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by flash column chromatography (eluting with 0-15% methanol in dichloromethane) to give the title compound (220 mg, 74%); Mass spectrum: (DMS0-d6) 1.42 (s, 9H), 1.43 (s, 9H), 2.48 (ra, 2H), 3.55 (m, 2H), 4.02 (m, 2H), 6.31 (s, 1H) , 7.17 (m, 2H), 7.52 (m, 2H), 7.58 (d, 2H), 7.92 (d, 2H), 8.62 (s, 1H), 9.79 (s, 1H); Mass spectrum: M + H + 494.
Method 72 4-. { [(trifluoromethyl) sulfonyl] oxy} 3,4-dihydropyridine-l (2H) -butylcarboxylate A 1.6 M solution of n-butyllithium in hexanes (6.9 ml, 11 mmol) is added to a stirred solution of diisopropylamine (1.5 ml, 11 mmol) in THF a -78 ° C and the mixture is stirred for 30 minutes. A solution of tert-butyl 4-oxipiperidin-l-carboxylate (2.0 g, 10 mmol) in THF and after 20 minutes a solution of N-phenyl-bis (trifluoromethanesulfonimide) (3.9 g, 11 mmol) in THF. The mixture is stirred at room temperature overnight and the solvent is evaporated. He - - The resulting residue is partitioned between diethyl ether and a sodium hydroxide solution, the organic layer is separated, washed once with brine and dried over magnesium sulfate, filtered and evaporated to give the compound of the title (3.01 g, 83%); NMR spectrum: (DMSO-ds) 1.48 (s, 9H), 2.44 (m, 2H), 3.63 (t, 2H), 4.04 (d, 2H), 5.76 (s, 1H).
Method 73 1-bromoacetyl-1,2,3-tetrahydroquinoline 1, 2, 3, 4-tetrahydroquinoline (10 g, 75 mmol) is dissolved in 40 ml of benzene and cooled to 10 ° C. A solution of bromoacetyl bromide (16 g, 80 mmol) in 40 ml of benzene is added dropwise over 1 hour. The mixture is stirred for an additional 15 minutes. 500 ml of a 2M aqueous solution of sodium hydroxide are added. The organic layer is separated, washed with 100 ml of water, dried over magnesium sulfate and evaporated to give the crude product as an oil. This is purified by distillation under reduced pressure followed by recrystallization from petroleum ether 60-80 to provide the product as a colorless solid (12.5 g, 66%). Analysis calculated for CnHi20 Br provides C 52.0%, H 4.8%, N 5.5%, Br 31.4%; found C 51.9%, 4.8%, N 5.6%, Br 30.9%.
Methods 74-75 Using a procedure analogous to that described in Method 4, N- (2-tert-butoxycarbonylaminophenyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) is reacted benzamide (Method 13) with the chloroheterocycle requirement to provide the compounds described in Table 17 Table 17 R1 Analytical data SM Method 74 Mass spectrum: M + H + Meth 76 446. 75 NMR spectrum: (DMS0-ds) 1.47 (s, 9H), 7.21 (m, 2H), 7.58 (m, 2H), 7.78 (d, IH), 8.12 (d, IH), 8.19 (m, 4H) , 8.71 (s, IH), 9.23 (s, IH), 10.01 (s, IH); Mass spectrum: M + H + 347.
Method 76 7-chlorothieno [3,2- b] pyridine. ~~ Thiene [3, 2, b] pyridin-7-ol (200 mg, 1.32 mraole) is added to thionyl chloride (1.57 g, 13.2 mmol), followed by one drop of DMF. The solution is stirred at 80 ° C for 4 hours. The cooled solution is diluted with ethyl acetate and neutralized to pH 7 with 25 ml of a saturated sodium hydrogen carbonate solution. The organic layer is washed with brine, dried and concentrated to provide the title compound (112 mg, 50%); Mass spectrum: M + H + 170.

Claims (12)

1. A compound of the formula (I): (I) wherein: the ring A is a heterocyclyl, wherein if the heterocyclyl contains an -NH- portion, this nitrogen may be optionally substituted by a group selected from K R1 is a substituent on the carbon and is selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy from 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) ) 2-amino, alkanoylamino of 1 to 6 carbon atoms, N-alkylcarbamoyl of 1 to 6 carbon atoms,?,? - (alkyl of 1 to 6 carbon atoms) 2-carbamoyl, alkylS (0) of 1 to 6 carbon atoms, where a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms, N- (alkylsulfamoyl of 1 to 6 carbon atoms) sulfam oyl, N, N- (C 1-6 alkyl) 2-sulfamoyl, aryl, aryloxy, arylalkyl of 1 to 6 carbon atoms, a heterocyclic group, (heterocyclic group) -alkyl of 1 to 6 carbon atoms or a group (BE-), wherein R1 includes a group (BE-), which may optionally be substituted on the carbon by one or more of; and wherein, if the heterocyclic group contains a -NH- portion, that nitrogen may be optionally substituted by J; W is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms , alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 atoms carbon) 2-amino, alkanoylamino of 1 to 6 carbon atoms, N- (alkyl of 1 to 6 carbon atoms) carbamoyl, N, N- (alkyl of 1 to 6 carbon atoms) 2-carbamoyl, alkylS (O) a of 1 to 6 carbon atoms, wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms, N-alkylsulfamoyl of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2-sulfamoyl or a group (B'-E'-); wherein W which includes the group (B'-E1-), optionally may be substituted on the carbon by one more than Y; Y and Z are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, N, N- (alkyl) from 1 to 6 carbon atoms) 2-amino, alkanoylamino of 1 to 6 carbon atoms, N-alkylcarbamoyl of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2-carbamoyl, alkylS ( 0) a of 1 to 6 carbon atoms, wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms, N-alkylsulfamoyl of 1 to 6 carbon atoms or N, N- (alkyl of 1 to 6 atoms) carbon) 2-sulfamoyl; G, J and K are independently selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkanoyl of 1 to 8 carbon atoms, alkylsulfonyl of 1 to 8 carbon atoms, alkoxycarbonyl of 1 to 8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 1 to 8 carbon atoms, N, N- (alkyl of 1 to 8 carbon atoms) 2-carbamoyl, benzyloxycarbonyl, benzoyl, phenylsulfonyl, aryl, arylalkyl of 1 to 6 carbon atoms or (heterocyclic group) alkyl of 1 to 6 carbon atoms; wherein G, J and K may be optionally substituted on the carbon by one or more of Q; and wherein if said heterocyclic group contains an -H- moiety, the nitrogen may be optionally substituted by hydrogen or alkyl of 1 to 6 carbon atoms; Q is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms , alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 atoms carbon) 2-amino, alkanoylamino of 1 to 6 carbon atoms, N-alkylcarbamoyl of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2-carbamoyl, alkylS (0) of 1 to 6 carbon atoms, wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms, alkoxycarbonylamino of 1 to 6 carbon atoms, N-alkylsulfamoyl of 1 to 6 carbon atoms, N, N- (alkyl) 1 to 6 carbon atoms) 2-sulfamoyl, aryl, aryloxy, arylalkyl of 1 to 6 carbon atoms, arylalkoxy of 1 to 6 carbon atoms, a heterocyclic group, (heterocyclic group) -alkyl uilo of 1 to 6 carbon atoms, (heterocyclic group) alkoxy of 1 to 6 carbon atoms or a group (B "-E" -) (- where Q, which includes the group (B "-E" -) it may be optionally substituted on the carbon by one or more of Z; B, B 'and B "are independently selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl (of 3 to 8 carbon atoms) -alkyl of 1 to 6 carbon atoms, aryl, arylalkyl of 1 to 6 carbon atoms, a heterocyclic group (heterocyclic group) -alkyl of 1 to 6 carbon atoms, phenyl or phenylalkyl of 1 to 6 carbon atoms, wherein B, B 'and B "may optionally be substituted on the carbon by one or more of D; and wherein if the heterocyclic group contains an -NH- moiety, that nitrogen may be optionally substituted by a group selected from G; E, E 'and E "are independently selected from -N (Ra) -, -O-, -C (0) 0-, -OC (0) -, -C (0) -, -N (Ra) C (0) -, -N (Ra) C (0) N (Rb) -, -N (Ra) C (0) 0-, -0C (0) N (R) -, -C (0) N ( Ra) -, -S (0) r-, -SOzN (Ra) -, -N (Ra) S02, wherein R and Rb are independently selected from hydrogen or alkyl of 1 to 6 carbon atoms, optionally substituted by one or more than F and r is 0-2; Eph and ~ F are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2-amino, alkanoylamino of 1 to 6 carbon atoms, N-alkylcarbamoyl of 1 to 6 carbon atoms, N, - (alkyl of 1 to 6 carbon atoms) 2- carbamoyl, alkylS (0) a of 1 to 6 carbon atoms, where a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms, N-alkylsulfamoyl of 1 to 6 carbon atoms or N, N- (alkyl of 1 to 6 carbon atoms) 2-sulfamoyl; m is 0, 1, 2, 3 or; wherein the values of R1 may be the same or different; R2 is halo; n is 0, 1 or 2; wherein the values of R2 may be the same or different; R3 is amino or hydroxy; R4 is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms, alkynyl of 2 to 3 carbon atoms , alkoxy of 1 to 3 carbon atoms, alkanoyl of 1 to 3 carbon atoms, alkanoyloxy of 1 to 3 carbon atoms', N-alkylamino of 1 to 3 carbon atoms, N, N- (alkyl of 1 to 3 carbon atoms) 2-amino, alkanoylamino of 1 to 3 carbon atoms, N-alkylcarbamoyl of 1 to 3 carbon atoms, N, N- (alkyl of 1 to 3 carbon atoms) 2-carbamoyl, alkylS (0) of 1 to 3 carbon atoms, wherein a is 0 to 2, alkoxycarbonyl of 1 to 3 carbon atoms, N- (alkyl of 1 to 3 carbon atoms) sulfamoyl, N, N- (alkyl of 1 to 3 carbon atoms) carbon) 2-sulfamoyl; p is 0, 1 or 2; wherein the values of R4 may be the same or different; or a pharmaceutically acceptable salt or an ester or amide hydrolysable in vivo thereof; with the proviso that the compound is not N- (2-amino-6-hydroxyphenyl) -4- (1-methylhomo-piperazin-4-yl) benzamide; N- (2-amino-6-methylphenyl) -4- (1-methylhomopiperazin-4-yl) benzamide; N- (2-Aminophenyl) -4- (1-tert-butoxycarbonyl-homopiperazin-4-yl) -benzamide; or N- (2-aminophenyl) -4- (l-methylhomopiperazin-4-yl) benzamide.
2. A compound of the formula (I), as described in claim 1, wherein: ring A is pyridyl, quinolyl, indolyl, pyrimidinyl, morpholinyl, piperidinyl, piperazinyl, pyrazinyl, pyrazinyl, thiazolyl, thienyl, thienopyrimidinyl, thienopyridinyl. , purinyl, triazinyl, oxazolyl, pyrazolyl, or furanyl; wherein if the ring A contains a portion -NH-, that nitrogen may be optionally substituted by a group selected from K.
3. The compound of the formula (I), as described in claim 1, wherein: R1 is a substituent on the carbon and is selected from halo, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, aryl, aryloxy, arylalkyl 1 to 6 carbon atoms, a heterocyclic group, (heterocyclic group) -alkyl of 1 to 6 carbon atoms or a group (BE-), wherein R 1 includes a group (BE-), which may be optionally substituted on the carbon by one or more of W; and wherein, if the heterocyclic group contains a -NH- portion, that nitrogen may be optionally substituted by J; W is hydroxy, mercapto, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2amino, or a group (B'-E1-); wherein C "includes the group (B'-E1-), optionally may be substituted on the carbon by one more than Y; Y and Z are independently selected from halo, nitro, cyano, hydroxy, alkoxy of 1 to 6 carbon atoms; carbon, N, N- (alkyl of 1 to 6 carbon atoms) 2-amino or alkanoylamino of 1 to 6 carbon atoms; G, J and K are independently selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkanoyl of 1 to 8 carbon atoms, aryl, arylalkyl of 1 to 6 carbon atoms or (heterocyclic group) alkyl of 1 to 6 carbon atoms, wherein G, J and K may be optionally substituted on the carbon per one or more of Q; and wherein if said heterocyclic group contains a -NH- portion, the nitrogen may optionally be substituted by hydrogen or alkyl of 1 to 6 carbon atoms; Q is cyano, hydroxy, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alco xicarbonylamino of 1 to 6 carbon atoms, aryl, aryloxy or a group (B "-E" -); wherein Q, which includes the group (B "-E" -) may optionally be substituted on the carbon by one or more of Z; B, B 'and B "are independently selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms) -alkyl of? To 6 carbon atoms, 5 aryl, arylalkyl of 1 to 6 carbon atoms, a heterocyclic group, (heterocyclic group) -alkyl of 1 to 6 carbon atoms, phenyl or phenylalkyl from 1 to 6 carbon atoms, wherein B, B 'and B "can optionally be substituted on the carbon by one or more of D; and wherein if the heterocyclic group contains an -NH- moiety, that nitrogen may be optionally substituted by a group selected from G; E, E1 and E "are independently selected from -N (Ra) -, -O-, -C (0) 0-, -OC (0) -, -C (O) -, -N (Ra) C ( 0) -,: 5 -N (Ra) C (0) N (Rb) -, -N (Ra) C (0) 0-, -0C (0) N (R) -, -C (0) N (Ra) -, -S (0) r-, -S02N (Ra) -, -N (Ra) S02, wherein R and Rb are independently selected from hydrogen or alkyl of 1 to 6 carbon atoms, optionally substituted by one or more of F and r is 0-2; 0 D and F are independently selected halo, alkoxy of 1 to 6 carbon atoms or N, N- (alkyl of 1 to 6 carbon atoms) 2-amino. compound of formula (I), as described in claim 1, wherein m is 1. 5. The compound of formula (I), as described in claim 1, wherein R2 is fluoro and n is 0 or 1 6. The compound of formula (I), as described in claim 1, wherein R3 is amino 7. The compound of formula (I), as described in claim 1, wherein p is 0. 8 The compound of formula (I), as described in claim 1, wherein: the ring A is pyridyl, quinolyl, indolyl, pyrimidinyl, morpholinyl, piperidinyl, piperazinyl, pyrazinyl, pyrazinyl, thiazolyl, thienyl, thienopyrimidinyl, thienopyridinyl, purinyl, triazinyl, oxazolyl, pyrazolyl, or furanyl.; wherein if the ring A contains a portion -NH-, that nitrogen may be optionally substituted by a group selected from K; R1 is a substituent on carbon and is selected from halo, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, aryl, aryloxy, arylalkyl 1 to 6 carbon atoms, a heterocyclic group, (heterocyclic group) -alkyl of 1 to 6 carbon atoms or a group (BE-), wherein R 1 includes a group (BE-), which may be optionally substituted on the carbon per one or more of W and wherein, if the heterocyclic group contains an -NH- portion, that nitrogen may be optionally substituted by J; W is hydroxy, mercapto, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2amino, or a group (B'-E1-); wherein W which includes the group (B'-E1-), can optionally be substituted on the carbon by one more than Y; Y and Z are independently selected from halo, nitro, cyano, hydroxy, alkoxy of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) 2-amino or alkanoylamino of 1 to 6 carbon atoms; G, J and K are independently selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkanoyl of 1 to 8 carbon atoms, aryl, arylalkyl of 1 to 6 carbon atoms or (heterocyclic group) ) alkyl of 1 to 6 carbon atoms; wherein G, J and K may be optionally substituted on the carbon by one or more of Q; and wherein if said heterocyclic group contains an -NH- moiety, the nitrogen may be optionally substituted by hydrogen or alkyl of 1 to 6 carbon atoms; Q is cyano, hydroxy, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, alkoxycarbon of 1 to 6 carbon atoms, alkoxycarbonylamino of 1 to 6 carbon atoms, aryl, aryloxy or a group (B "-AND"-); wherein Q, which includes the group (B "-E" -) may optionally be substituted on the carbon by one or more of Z; B, B 'and B "are independently selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms) -alkyl of 1 to 6 carbon atoms, aryl, arylalkyl of 1 to 6 carbon atoms, a heterocyclic group, (heterocyclic group) -alkyl of 1 to 6 carbon atoms, phenyl or phenylalkyl of 1 to 6 carbon atoms, wherein B, B1 and B "can optionally be substituted on the carbon by one or more of D; and wherein if the heterocyclic group contains an -NH- moiety, that nitrogen may be optionally substituted by a group selected from G; E, E1 and E "are independently selected from -N (Ra) -, -0-, -C (0) 0-, -OC (0) -, -C (0) -, -N (Ra) C ( 0) -, -N (Ra) C (0) N (Ra) -, -N (Ra) C (0) 0-, -0C (O) N (Ra) -, -C (O) N (Ra ) -, -S (0) r-, -S02N (Ra) -, -N (Ra) S02, wherein Ra and Rb are independently selected from hydrogen or alkyl of 1 to 6 carbon atoms, optionally substituted by one or more than F and r is 0-2; D and F are independently selected halo, C 1-6 alkoxy or N, N- (C 1-6 alkyl) 2-amino; - "-" ". m is OT "1, 2, 3 or 4, wherein the values of R1 may be the same or different, R2 is fluoro or chloro, 5 n is 0, 1 or 2, where R2 values may be the same or different R3 is amino or hydroxy, R4 is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy or carbamoyl, p is 0, 1 or 2, wherein the values of R4 may be the same or different; pharmaceutically acceptable salt or an in vivo hydrolysable ester or amide thereof 9. The compound of formula 1, as described in claim 1, wherein: ring A is pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, quinolin-8-yl, pyrimidin-6-yl, pyrimidin-5-yl, pyrimidin-4-yl, morpholin-4-yl, piperidin-4-yl, piperidin-3-yl, piperidin -2-yl, piperazin-4-yl, pyridazin-5-yl, pyrazin-6-yl, thiazol-2-yl, thieno-2-yl, thieno [3, 2d] pyrimidinyl, thieno [3, 2b] irimidinyl , thieno [3, 2b] iridinyl, purin-6-yl or triazin-6-yl; wherein if ring A contains a portion -NH-, that nitrogen may be optionally substituted by a group selected from K; R1 is a substituent on carbon and is selected from fluoro, chloro, amino, methyl, ethyl, propyl, methoxy, N-methylamino, N-ethylamino, N-propylamino, N-butylamino, phenyl, naphthylethyl, piperazin-1- ilo, piperidin-1-yl, piperidin-4-yl, 2- (thiomethyl) -pyrimidin-4-yl, tetrahydrofuran-2-ylmethyl, tetrahydropyran-2-ylmethyl, 1, 2, 5-thiadiazol-3-ethylthyl, piperidin-1-ylmethyl, pyridin-2-ylmethyl or a group (BE-); wherein R1, which includes the group (B-E-), which may be optionally substituted on the carbon by one or more of; and wherein, if the heterocyclic group contains a -NH- portion, that nitrogen may be optionally substituted by J; is hydroxy, methyl, ethyl, ethoxy, N, N- (diethyl) amino, N, N- (dibutyl) amino or a group (B'-E1-); wherein W which includes the group (B'-E1-), can optionally be substituted on the carbon by one more than Y; Y and Z are independently selected from fluoro, chloro, bromo, nitro, cyano, hydroxy, methoxy, N, N- (dimethyl) amino or methylcarbonylamino; G, J and K are independently selected from methyl, ethyl, propyl, pentyl, 2-methyl butyl, butyl, acetyl, benzyl, 3- (pyrrol-1-yl) propyl or pyrrolidin-2-one- (5S) -methyl; wherein G, J and K may be optionally substituted on the carbon by one or more of Q; wherein if the heterocyclic group contains a portion -NH- that nitrogen "may optionally be substituted by hydrogen or methyl; Q is cyano, 'hydroxy, methoxy, ethoxy, methylcarbonyloxy, methoxycarbonyl, terbutoxycarbonylamino, phenyl or a group (B" -E "-), wherein Q, which includes the group (B" -E "-), may optionally be substituted on the carbon by one or more Z; B, B 'and B" are independently selected from methyl, ethyl, propyl , cyclohexyl, phenyl, benzyl, 1, 2, 3, 4-tetrahydroquinolinyl, 3-morpholinopropyl, 2-morpholinoethyl, 2-pyrrolidin-1-ylethyl, 3-morpholinopropyl, 3- (4-methylpiperazin-1-yl) propyl, 2-piperidin-1-ylethyl, 3-piperidin-1-ylpropyl, pyridin-3-ylmethyl or imidazol-1-ylpropyl; wherein B, B 'and B "may be optionally substituted on the carbon by one or more of D, and wherein if the heterocyclic group contains an -NH- portion, that nitrogen may be optionally substituted by a group selected from G; E, E1 and E "are independently selected from - (Ra) -, -O-, -NHC (O) -, -N (Ra) C (0) 0-; wherein Ra is hydrogen or methyl optionally substituted by one or more of F; D and F are independently selected from fluoro, methoxy or ethoxy; m is 0, 1 or 2; wherein the values of R1 may be identical or different; R2 is fluoro; n is 0 or 1; R3 is amino; R4 is halo; p is 0, 1 or 2, wherein the values of R4 may be the same or different; or a pharmaceutically acceptable salt or an ester or amide hydrolysable in vivo thereof. 10. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, as described in claim 1, which process comprises: (a) reacting a compound of the formula (II) wherein X is a reactive group, with a compound of the formula (III) wherein L1 and L2 are ligands; (b) The reaction of a compound of the formula (IV) wherein L1 and L2 are ligands, with a compound of the formula (V) wherein X is a reactive group; or (c) the reaction, in the presence of 4- (4,6-dimethoxy-1,3,5-triazinyl-2-yl) -4-methylmorpholinium chloride of a compound of the formula (VI) with a compound of the formula (VII) < Rl). GO')" (vile) and subsequently, if necessary: i) converting a compound of formula (I) to another compound of formula (I); and / or ii) removing any protecting group. 11. A pharmaceutical composition, comprising a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof, as described in claims 1 to 9, in association with a pharmaceutically acceptable diluent or carrier. . 12. A compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester or amide thereof, as described in claims 1 to 9, for use as a medicament. T.3. The use of a compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester or amide thereof, as described in claims 1 to 9, in the manufacture of a medicament for use in the production of an inhibitory effect of HDAC in a homeothermic animal such as man. A method for producing an HDAC inhibitory effect in a homeothermic animal, such as man, in need of such treatment, which comprises administering to the animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester or amide thereof, as described in claims 1 to 9. 15. The use of a compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester or amide thereof , as described in claims 1 to 9, in the manufacture of a medicament for use in the treatment of cancer. 16. A method for treating cancer in a homeothermic animal, such as man, in need of such treatment, which comprises administering to the animal an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or ester or In vivo hydrolysable amide thereof, as described in claims 1 to 9. ~~~ G7? The use _of ^ a? compound of the formula (I), or a pharmaceutically acceptable salt or an ester or amide hydrolysable in vivo thereof, as described in claims 1 to 9, for use in the treatment of cancer.
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